Alternative titles; symbols
HGNC Approved Gene Symbol: IL6
Cytogenetic location: 7p15.3 Genomic coordinates (GRCh38): 7:22,727,200-22,731,998 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p15.3 | {Crohn disease-associated growth failure} | 266600 | Multifactorial | 3 |
| {Intracranial hemorrhage in brain cerebrovascular malformations, susceptibility to} | 108010 | Somatic mutation | 3 | |
| {Kaposi sarcoma, susceptibility to} | 148000 | Autosomal dominant | 3 | |
| {Rheumatoid arthritis, systemic juvenile} | 604302 | 3 | ||
| {Type 1 diabetes mellitus} | 222100 | Autosomal recessive | 3 | |
| {Type 2 diabetes mellitus} | 125853 | Autosomal dominant | 3 |
IL6 is an immunoregulatory cytokine that activates a cell surface signaling assembly composed of IL6, IL6RA (IL6R; 147880), and the shared signaling receptor gp130 (IL6ST; 600694) (Boulanger et al., 2003).
Weissenbach et al. (1980) cloned a cDNA for a 1.3-kb mRNA, designated IFNB2, that was distinct from IFNB1 (147640) and produced biologically active interferon in induced human fibroblasts. The IFNB2 mRNA did not cross-hybridize with IFNB1 cDNA probes, and vice versa.
Zilberstein et al. (1986) cloned a full-length cDNA for IFNB2. In vitro transcription and translation showed that it encodes a 212-amino acid protein with a calculated molecular mass of 23.7 kb. IFNB2 has 2 putative glycosylation sites and a highly hydrophobic 30-amino acid N terminus, suggesting it is probably processed prior to secretion.
Hirano et al. (1986) obtained a full-length cDNA encoding human BSF2. The deduced protein contains 212 amino acids, including a 28-amino acid N-terminal signal peptide. The mature 184-amino acid protein has a calculated molecular mass of 20.7 kD. BSF2 purified from human T cells had an apparent molecular mass of 21 kD by SDS-PAGE. Northern blot analysis detected a 1.3-kb mRNA in activated lymphocytes and T cells, but not in unstimulated lymphocytes. As discussed by Sehgal et al. (1987), IFNB2 is identical to BSF2. It is also identical to HGF, which had been shown to enhance proliferation of hybridoma and plasmacytoma cells.
Sehgal et al. (1986) mapped the IFNB2 gene to chromosome 7 by means of a cDNA clone in blot-hybridization experiments on DNA from a panel of human-rodent somatic cell hybrids. Chen et al. (1987) and Ferguson-Smith et al. (1988) localized the IFNB2 gene to chromosome 7p21-p15 by in situ hybridization and Southern analysis of somatic cell hybrids. Using linkage studies with RFLPs and other mapping approaches, Bowcock et al. (1988) assigned the IL6 gene to chromosome 7p21. By in situ hybridization and Southern blot analysis of mouse-human hybrid cell lines, Sutherland et al. (1988) mapped the IL6 gene to chromosome 7p15.
Boulanger et al. (2003) solved the crystal structure of the IL6-IL6R-gp130 extracellular signaling complex to 3.65-angstrom resolution, which revealed a hexameric, interlocking assembly mediated by a total of 10 symmetry-related, thermodynamically coupled interfaces. Assembly of the hexameric complex occurred sequentially: IL6 was first engaged by IL6R and then presented to gp130 in the proper geometry to facilitate a cooperative transition into the high-affinity, signaling-competent hexamer. Boulanger et al. (2003) suggested that the quaternary structures of other IL6/IL12 (see 161560) family signaling complexes are likely constructed by means of a similar topologic blueprint.
Expression studies by Zilberstein et al. (1986) showed that IFNB2 secreted by DNA-transformed rodent cells was a processed 21-kD protein whose activity was cross-neutralized by antibodies to human IFNB1, but not to alpha-interferon (IFNA1; 147660) or gamma-interferon (IFNG; 147570). IFNB2 was induced under conditions in which IFNB1 was not induced, as in metabolically stressed cells. Induction of IFNB2 by IL1 (147720) and TNF (191160) suggested that it may play a role as an autocrine mediator of some effects of these cytokines in inflammation and acute phase responses, as well as regulate cell proliferation.
Tosato et al. (1988) identified IFNB2 as a monocyte-derived factor that promoted growth of Epstein-Barr virus-infected B cells.
Kawano et al. (1988) presented evidence that constitutive expression of BSF2 or its receptor may be responsible for generation of myelomas (254500). Aberrant production of IL6 by neoplastic cells has been implicated as a strong contributory factor to the growth of multiple myeloma and other B-cell dyscrasias, T-cell lymphoma, renal and ovarian cell carcinomas, and Kaposi sarcoma.
Santhanam et al. (1991) demonstrated repression of the IL6 gene promoter by p53 (191170) and RB1 (614041).
In Paget disease of bone (167250), osteoclasts are greatly increased in number and size and have increased numbers of nuclei per cell compared to normal osteoclasts. Roodman et al. (1992) found that conditioned media from long-term bone marrow cultures from patients with Paget disease stimulated formation of osteoclast-like multinucleated cells in normal marrow cultures. At least part of this activity could be ascribed to IL6. Normal bone marrow plasma and peripheral blood serum had no or very low levels of IL6. On the other hand, bone marrow from 7 of 8 involved bones and 18 of 27 peripheral blood serum samples from Paget patients had high levels of IL6.
Among 82 patients with cancer observed in 1993, Chung et al. (1996) found 3 with persistent hyperkalemia that could not be attributed to renal failure, pseudohyperkalemia, or drugs. They demonstrated that there was a selective impairment of aldosterone secretion and that all 3 patients had high plasma IL6 concentration. Chung et al. (1996) concluded that the 3 patients had cancer-related hyperreninemic hypoaldosteronism associated with the high IL6 concentrations. Antitumor therapy reduced plasma IL6 concentrations and improved the hyperkalemia in 1 patient and in vitro observations indicated that IL6 inhibited the secretion of aldosterone by adrenal tissue.
Redwine et al. (2000) evaluated the effects of nocturnal sleep, partial night sleep deprivation, and sleep stages on circulating concentrations of IL6 in relation to the secretory profiles of GH (see 139250), cortisol, and melatonin. Sleep onset was associated with an increase in serum levels of IL6 during baseline sleep. Sleep stage analyses indicated that the nocturnal increase in IL6 occurred in association with stage 1-2 sleep and rapid eye movement sleep, but levels during slow wave sleep were not different from those while awake. The profile of GH across the 2 nights was similar to that of IL6, whereas the circadian-driven hormones cortisol and melatonin showed no concordance with sleep. The authors concluded that loss of sleep may serve to decrease nocturnal IL6 levels, with effects on the integrity of immune system functioning. Alternatively, given the association between sleep stages and IL6 levels, depressed or aged populations who show increased amounts of REM sleep and a relative loss of slow wave sleep may have elevated nocturnal concentrations of IL6 with implications for inflammatory disease risk.
Scheidt-Nave et al. (2001) studied the role of serum IL6 as a predictor of bone loss in a population-based longitudinal study of 137 postmenopausal German women, who were 52 to 80 years old at baseline. Serum IL6 and other biochemical parameters were measured in baseline blood or urine specimens. Repeat standardized measures of bone mineral density (BMD) at the femur (total hip) and the lumbar spine (L2-L4) were taken by dual x-ray absorptiometry at an average of 3.3 years apart. Statistical interaction between serum IL6 and menopausal age or menopausal age group indicated that the effect of IL6 on bone loss weakened with increasing distance from menopause and was no longer significant in women more than 10 years after menopause. Among 39 women up to 10 years past menopause, serum IL6 was the single most important predictor of femoral bone loss, accounting for up to 34% of the total variability of change in BMD. The authors concluded that serum IL6 is a predictor of postmenopausal bone loss, and that the effect appears to be most relevant through the first postmenopausal decade.
Funatsu et al. (2002) investigated the relationship between diabetic macular edema and the levels of vascular endothelial growth factor (VEGF; 192240) and IL6 in aqueous humor and plasma. They found that aqueous levels of VEGF and IL6 correlated significantly with the severity of macular edema and that aqueous levels were significantly higher than plasma levels. In addition, the aqueous level of VEGF correlated significantly with that of IL6. The authors concluded that both VEGF and IL6 are produced together in the intraocular tissues and that both are involved in the pathogenesis of diabetic macular edema.
De Groof et al. (2002) evaluated the GH/IGF1 (147440) axis and the levels of IGF-binding proteins (IGFBPs), IGFBP3 protease (146732), glucose, insulin (176730), and cytokines in 27 children with severe septic shock due to meningococcal sepsis during the first 3 days after admission. The median age was 22 months. Significant differences were found between nonsurvivors and survivors for the levels of total IGF1, free IGF1, IGFBP1, IGFBP3 protease activity, IL6, and TNFA. The pediatric risk of mortality score correlated significantly with levels of IGFBP1, IGFBP3 protease activity, IL6, and TNFA and with levels of total IGFI and free IGFI. Levels of GH and IGFBP1 were extremely elevated in nonsurvivors, whereas total and free IGFI levels were markedly decreased and were accompanied by high levels of the cytokines IL6 and TNFA.
Pasare and Medzhitov (2003) found that microbial induction of dendritic cell (DC) maturation by activation of Toll-like receptors (e.g., TLR4; 603030) abrogated the suppressive effects of CD25 (147730)-positive/CD4 (186940)-positive regulatory T (Tr) cells. The blockade of Tr cell-mediated suppression was independent of costimulatory molecule expression on DCs. Stimulation of the TLR/MYD88 (602170) pathway in DCs led to the expression of IL6 and, most likely, other secreted factors that do not signal through the common gamma chain (IL2RG; 308380), and these mediated the block of suppression. Il6-deficient mice were severely compromised in the induction of effector T-cell responses, and this defect could be transiently overcome by depletion of Tr cells. Pasare and Medzhitov (2003) concluded that the failure of Il6-deficient mice to overcome Tr-mediated suppression resulted in increased susceptibility to infection and resistance to autoimmunity. In a commentary, Powrie and Maloy (2003) proposed a model for the control of Tr development by innate immune cells and noted that the targeting of IL6 may be an attractive treatment for inflammatory diseases.
To describe the pattern of change in IL6 over 6 years among older adults undergoing a chronic stressor, Kiecolt-Glaser et al. (2003) used a longitudinal community study to assess the relationship between chronic stress and IL6 production in 119 men and women who were caregiving for a spouse with dementia and 106 noncaregivers, with a mean age at study entry of 70.58 years for the full sample. On entry into this portion of the longitudinal study, 28 of the caregivers' spouses had already died, and an additional 50 of the 119 spouses died during the 6 years of this study. Levels of IL6 and health behaviors associated with IL6 were measured over 6 years. Caregivers' average rate of increase in IL6 was about 4 times as large as that of noncaregivers. Moreover, the mean annual changes in IL6 among former caregivers did not differ from that of current caregivers even several years after the death of the impaired spouse. There were no systematic group differences in chronic health problems, medications, or health-relevant behaviors that might have accounted for caregivers' steeper IL6 slope. These data provided evidence of a key mechanism through which chronic stressors may accelerate risk of a host of age-related diseases by prematurely aging the immune response.
Viereck et al. (2003) demonstrated that raloxifene inhibited production of the bone-resorbing cytokine IL6 and stimulated production of osteoprotegerin (OPG; 602643) by human osteoblasts. Raloxifene inhibited expression of IL6 by 25 to 45% (P less than 0.001).
In a prospective study of 251 individuals aged 60 or older who had some sign of nonexudative age-related macular dystrophy (ARMD; see 603075), Seddon et al. (2005) found that higher levels of C-reactive protein (CRP; 123260) and IL6 were independently associated with progression of ARMD.
Nemeth et al. (2004) added IL6-neutralizing antibodies to hepatocyte cultures and completely ablated the hepcidin (606464) increase induced by lipopolysaccharide or lipopolysaccharide-induced macrophages. Turpentine abscesses significantly induced hepcidin mRNA in wildtype mice (9.3-fold increase) compared to Il6-knockout mice (1.9-fold increase; p less than 0.001). However, the authors found that Il6 was not required in the regulation of hepcidin mRNA by iron, since there was no significant difference between wildtype and knockout mice in the hepcidin response to iron refeeding. In humans, infusion of IL6 rapidly increased hepcidin excretion with a concomitant decrease in serum iron and transferrin saturation. Nemeth et al. (2004) concluded that IL6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL6-hepcidin axis is responsible for the hypoferremia of inflammation.
Liuzzi et al. (2005) found that Zip14 (SLC39A14; 608736) was the most upregulated zinc transporter in response to turpentine-induced inflammation or LPS in mouse liver. Il6 -/- mice exhibited neither hypozincemia nor Zip14 induction with turpentine-induced inflammation, and the hypozincemic response was milder in Il6 -/- mice exposed to LPS than in wildtype mice. Northern blot analysis revealed liver-specific upregulation of a single Zip14 transcript. Immunohistochemical analysis showed increased expression of Zip14 on the plasma membrane of hepatocytes in response to both LPS and turpentine. Il6 also produced increased expression of Zip14 in primary hepatocyte cultures and localization of the Zip14 protein to the plasma membrane. Transfection of mouse Zip14 cDNA into human embryonic kidney cells increased zinc uptake. Liuzzi et al. (2005) concluded that IL6 regulates the zinc importer ZIP14 and contributes to the hypozincemia accompanying the acute-phase response to inflammation and infection.
Normal intestinal mucosa contains abundant immunoglobulin A (IgA)-secreting cells, which are generated from B cells in gut-associated lymphoid tissues. Mora et al. (2006) showed that dendritic cells (DCs) from gut-associated lymphoid tissues induce T cell-independent expression of IgA and gut-homing receptors on B cells. Gut-associated lymphoid tissue DC-derived retinoic acid alone conferred gut tropism but could not promote IgA secretion. However, retinoic acid potently synergized with the gut-associated lymphoid tissue DC-derived IL6 or IL5 (147850) to induce IgA secretion. Mora et al. (2006) found that consequently, mice deficient in the retinoic acid precursor vitamin A lacked IgA-secreting cells in the small intestine. Mora et al. (2006) found that gut-associated lymphoid tissue DCs shape mucosal immunity by modulating B cell migration and effector activity through synergistically acting mediators.
TGF-beta (190180) converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of IL6, TGF-beta also promotes the differentiation of naive T lymphocytes into proinflammatory IL17 (see 603149) cytokine-producing T-helper 17 (Th17) cells, which promote autoimmunity and inflammation. This raises the question of how TGF-beta can generate such distinct outcomes. Mucida et al. (2007) identified the vitamin A metabolite retinoic acid as a key regulator of TGF-beta-dependent immune responses, capable of inhibiting the IL6-driven induction of proinflammatory Th17 cells and promoting antiinflammatory regulatory T cell (Treg) differentiation. Mucida et al. (2007) concluded that a common metabolite can regulate the balance between pro- and antiinflammatory immunity.
Ghoreschi et al. (2010) showed that Th17 differentiation can occur in the absence of TGF-beta signaling. Neither IL6 nor IL23 (see 605580) alone efficiently generated Th17 cells; however, these cytokines in combination with IL1-beta (147720) effectively induced IL17 production in naive precursors, independently of TGF-beta. Epigenetic modification of the IL17A, IL17F (606496), and RORC (602943) promoters proceeded without TGF-beta-1, allowing the generation of cells that coexpressed ROR-gamma-t (encoded by RORC) and Tbet (TBX21; 604895). Tbet+ROR-gamma-t+Th17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred Th17 cells generated with IL23 without TGF-beta-1 were pathogenic in this disease model. Ghoreschi et al. (2010) concluded that their data indicated an alternative mode for Th17 differentiation, and that, consistent with genetic data linking IL23R with autoimmunity, their findings reemphasized the importance of IL23 and therefore may have therapeutic implications.
Ancrile et al. (2007) found that expression of an oncogenic form of HRAS (190020) induced secretion of IL6 in normal primary human kidney cells, fibroblasts, myoblasts, and mammary epithelial cells. Knockdown of IL6, genetic ablation of the Il6 gene in mice, or treatment with IL6-neutralizing antibody retarded HRAS-driven tumorigenesis. IL6 appeared to act in a paracrine fashion to promote angiogenesis and tumor growth.
The Mediterranean diet, a dietary pattern typical of regions in Greece and southern Italy in the early 1960s, is protective against cardiovascular disease, possibly due to reduced systemic inflammation. Dai et al. (2008) studied 345 monozygotic and dizygotic middle-aged male twins and found that adherence to the Mediterranean diet was associated with reduced fasting plasma levels of IL6, but not CRP, after adjustments for total energy intake, other nutritional factors, cardiovascular risk factors, and use of supplements and medication. When the overall association of adherence to the diet with IL6 levels was partitioned into between- and within-pair effects, the between-pair effect was not significant, whereas the within-pair effect was highly significant. A 1-unit within-pair absolute difference in diet-adherence score was associated with a 9% lower IL6 level. Dai et al. (2008) concluded that reduced inflammation, as measured by IL6 level, is an important mechanism linking the Mediterranean diet to reduced cardiovascular risk.
Sabio et al. (2008) explored the mechanism of JNK1 (601158) signaling by engineering mice in which the Jnk1 gene was ablated selectively in adipose tissue. JNK1 deficiency in adipose tissues suppressed high-fat diet-induced insulin resistance in the liver. JNK1-dependent secretion of IL6 by adipose tissue caused increased expression of liver SOCS3 (604176), a protein that induces hepatic insulin resistance. Sabio et al. (2008) concluded that JNK1 activation in adipose tissue can cause insulin resistance in the liver.
Meng et al. (2008) noted that altered expression of microRNAs (miRNAs) has been associated with cancer. Using miRNA expression profiling, they showed that malignant cholangiocytes overexpressing IL6 showed decreased expression of MIR370 (612553), whereas those incubated with a methylation inhibitor showed increased expression of MIR370. Meng et al. (2008) identified MAP3K8 (191195) as a target of MIR370, and MAP3K8 expression was decreased by the methylation inhibitor in cholangiocarcinoma cells. Overexpression of IL6 reduced MIR370 expression and reinstated MAP3K8 expression in vitro and in tumor cell xenografts in vivo. Meng et al. (2008) proposed that IL6 may contribute to tumor growth by epigenetic modulation of the expression of selected miRNAs, such as MIR370.
In studies in mice, Ellingsgaard et al. (2011) demonstrated that administration of IL6, or elevated Il6 concentrations in response to exercise, stimulated Glp1 (see 138030) secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. Il6 increased Glp1 production from alpha cells through increased proglucagon (see 138030) and prohormone convertase 1/3 (see 162150) expression. In mouse models of type 2 diabetes (125853), the beneficial effects of Il6 were maintained, and Il6 neutralization resulted in further elevation of glycemia and reduced pancreatic Glp1. Experiments using human islet cells showed that bioactive GLP1 released from human islets could improve insulin secretion in vitro, and that IL6 acts directly on alpha cells to enhance their ability to liberate GLP1. Ellingsgaard et al. (2011) concluded that IL6 mediates crosstalk between insulin-sensitive tissues, intestinal L cells, and pancreatic islets to adapt to changes in insulin demand.
Harker et al. (2011) reported that during a murine chronic viral infection, interleukin-6 was produced by irradiation-resistant cells in a biphasic manner, with late Il6 being absolutely essential for viral control. The underlying mechanism involved Il6 signaling on virus-specific CD4 (186940) T cells that caused upregulation of the transcription factor Bcl6 (109565) and enhanced T follicular helper cell responses at late, but not early, stages of chronic viral infection. This resulted in escalation of germinal center reactions and improved antibody responses.
Xu et al. (2011) identified MIR365 (MIR365A; 614735) as a direct negative regulator of IL6. Transfection of a DNA construct including the MIR365 precursor or a synthetic MIR365 mimic dose-dependently inhibited expression of an IL6 reporter in HEK293 cells and inhibited stimulant-induced secretion of IL6 from HeLa cells. An anti-MIR365 construct had opposite effects. Neither the MIR365 mimic nor the MIR365 inhibitor affected IL6 mRNA expression, suggesting that MIR365 inhibits IL6 translation. The IL6 3-prime UTR contains a putative binding site for the seed sequence of MIR365, and this binding site is widely conserved among vertebrates. Mutations within the binding site abrogated the effects of the MIR365 mimic and MIR365 inhibitor.
Zenker et al. (2014) found that Vav1 (164875) -/- mice had exacerbated disease, decreased survival, and evidence of pronounced organ damage in an experimental LPS-induced toxemia model compared with controls. Reconstitution of wildtype mice with Vav1 -/- macrophages led to higher susceptibility to LPS. Vav1 -/- macrophages, but not T cells, produced increased Il6, but not Tnf, in response to LPS in vitro and in vivo. Antibody to IL6r abrogated hypersensitivity to LPS endotoxemia. The authors showed that Il6 promoter activity was controlled by nuclear Vav1 interacting with Hsf1 (140580) at the heat shock element-2 (HSE2) region of the Il6 promoter. Zenker et al. (2014) suggested that targeting VAV1 may lead to better treatment of shock.
Zhang et al. (2015) showed that TET2 (612839) selectively mediates active repression of IL6 transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. Loss of TET2 resulted in the upregulation of several inflammatory mediators, including IL6, at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL6 production compared to wildtype mice. I-kappa-B-zeta (NFKBIZ; 608004), an IL6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of I-kappa-B-zeta at initial and resolution phases of inflammation. For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 (605164) and repressed transcription of Il6 via histone deacetylation. Zhang et al. (2015) concluded they provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.
By flow cytometric analysis, Zhang et al. (2016) demonstrated that the proportion of mouse B cells expressing Cd5 (153340) relative to those expressing Il6ra was greatly increased in tumors. Western blot analysis showed that Cd5-positive B cells responded to Il6 in the absence of Il6ra. Binding of Il6 to Cd5 led to Stat3 (102582) activation via gp130 and its downstream kinase Jak2 (147796). Stat3 upregulated Cd5 expression, forming a feed-forward loop in B cells. In mouse tumor models, Cd5-positive B cells, but not Cd5-negative B cells, promoted tumor growth. CD5-positive B cells also showed activation of STAT3 in multiple types of human tumor tissues. Zhang et al. (2016) concluded that CD5-positive B cells play a critical role in promoting cancer.
Chowdhury et al. (2020) found that IL6 regulated circulating osteocalcin (BGLAP; 112260) levels in response to training intervention in humans. Further analyses with mouse models showed that the majority of Il6 molecules present in general circulation during exercise originated from muscle. Muscle-derived Il6 enhanced exercise capacity by signaling in osteoblasts to promote osteoclast differentiation and release of osteocalcin in general circulation. Muscle-derived Il6 also favored uptake and catabolism of glucose and fatty acid in myofibers during exercise through osteocalcin. In addition, muscle-derived Il6 contributed to maintenance of muscle mass in an osteocalcin-independent manner.
Viral IL6
Chow et al. (2001) noted that Kaposi sarcoma-associated herpesvirus (KSHV, or HHV-8) encodes a functional homolog of IL6 (termed vIL6; 25% sequence homology) that is expressed in KSHV-infected cells and is able to induce angiogenesis and hematopoiesis in IL6-dependent cell lines. In contrast to IL6, which binds to gp130 only after it forms a complex with IL6RA, vIL6 directly activates gp130.
Suthaus et al. (2012) noted that HHV-8 is the etiologic agent not only of KS, but also of primary effusion lymphoma and plasma cell-type multicentric Castleman disease (MCD). They found that mice constitutively expressing vIL6 had Il6 levels comparable to those observed in HHV-8-infected patients and contained elevated amounts of phosphorylated Stat3 (102582) in spleen and lymph nodes, where vIL6 was produced. These mice also developed key features of MCD, such as splenomegaly, multifocal lymphadenopathy, hypergammaglobulinemia, and plasmacytosis. Upon transfer of the vIL6 gene to Il6-deficient mice, the MCD-like phenotype was not observed, suggesting that endogenous IL6 in the mouse is a critical cofactor in the disease. Suthaus et al. (2012) proposed that human IL6 plays an important role in the pathogenesis of HHV-8-associated MCD.
Fairfax et al. (2010) employed a combined approach of mapping protein and expression quantitative trait loci in peripheral blood mononuclear cells (PBMCs) using high-density SNP typing for about 2,000 loci implicated in cardiovascular, metabolic and inflammatory syndromes. Common SNP markers and haplotypes of the leptin gene (LEP; 164160) associated with a 1.7- to 2-fold higher level of lipopolysaccharide (LPS)-induced IL6 expression. Basal leptin expression significantly correlated with LPS-induced IL6 expression, and the same LEP variants that associated with IL6 expression were also major determinants of LEP expression in PBMCs. Variation involving 2 other genomic regions, CAPNS1 (114170) and ALOX15 (152392), showed significant association with IL6 expression. The same ALOX15 variants were associated with induced expression of tumor necrosis factor (TNF; 191160) and interleukin-1-beta (IL1B; 147720), consistent with a broader role in acute inflammation for ALOX15.
Bone Mineral Density
IL6 was one of the candidate genes chosen by Ota et al. (1999) for linkage studies of osteopenia and osteoporosis (166710) because the gene product stimulates osteoclasts through binding to its cell surface receptor, IL6R. Ota et al. (1999) studied 192 sib pairs of adult Japanese women from 136 families for genetic linkage between osteopenia and allelic variants of IL6, IL6R, calcium-sensing receptor (CASR; 601199), and matrix gla protein (154870), using as genetic markers dinucleotide-repeat polymorphisms present in or near each of these loci. The IL6 locus showed evidence of linkage to osteopenia analyzed as a qualitative trait, with mean allele sharing of 0.40 (P = 0.0001) in discordant pairs and 0.55 (P = 0.04) in concordant affected pairs. Variation at this locus was also linked to decreased bone mineral density measured as a quantitative trait (P = 0.02). Analyses limited only to postmenopausal women showed similar or even stronger results. No other locus among those tested showed any evidence of linkage by either method.
Ota et al. (2001) presented further evidence that variation in IL6 may be related to osteoporosis. In 470 Japanese subjects, they found a correlation between the presence of the G allele of a C/G polymorphism at nucleotide -634 and decreased bone mineral density (BMD), by analysis of variance. When BMD values were compared among the 3 genotypic groups at nucleotide -634, BMD was lowest among the GG homozygotes, highest among the CC homozygotes, and intermediate among the heterozygotes.
Chung et al. (2003) described a variant in the IL6 promoter region that showed positive association with higher BMD in a gene-dose-dependent manner in premenopausal women.
Systemic Juvenile Rheumatoid Arthritis
During active phases of systemic juvenile rheumatoid arthritis (604302), patients display a typical 'quotidian' (daily) spiking fever, an evanescent macular rash, lymphadenopathy, hepatosplenomegaly, serositis, myalgia, and arthritis. They are frequently anemic with markedly elevated neutrophil and platelet counts; they have a high erythrocyte sedimentation rate, C-reactive protein (123260), and serum fibrinogen (see 134820). The particularly unusual feature of acute systemic juvenile rheumatoid arthritis is the unique pattern of fever. Rooney et al. (1995) found that serum IL6 concentration rises significantly in conjunction with the fever spike, and then falls in parallel with the return of body temperature to normal. To explain the unique cyclic pattern of IL6 serum concentration in this disorder, Fishman et al. (1998) proposed that the regulation of the expression of IL6 in these patients differs from unaffected individuals, possibly as a result of 5-prime flanking region polymorphisms. They identified a G/C polymorphism at position -174 of the IL6 gene (147620.0001). In a group of 383 healthy men and women from a general practice in north London, the frequency of the C allele was 0.403 (95% CI 0.37-0.44). In comparison, 92 patients with systemic juvenile rheumatoid arthritis had a different overall genotype frequency, especially those with onset of disease under age 5 years. This was mainly due to the statistically significant lower frequency of the CC genotype in this group. When comparing constructs of the 5-prime flanking region in a luciferase reporter vector transiently transfected into HeLa cells, the -174C construct showed 0.624-fold lower expression than the -174G construct. After stimulation with lipopolysaccharide (LPS) or interleukin-1, expression from the -174C construct did not significantly change after 24 hours, whereas expression from the -174G construct increased by 2.35- and 3.60-fold, respectively, compared with the unstimulated level. Plasma levels of IL6 were also measured in 102 of the healthy subjects, and the C allele was found to be associated with significantly lower levels of plasma IL6. These results suggested that there is a genetically determined difference in the degree of the IL6 response to stressful stimuli between individuals. The reduced frequency of the potentially protective CC genotype in young systemic juvenile rheumatoid arthritis patients may contribute to its pathogenesis. Similarly, the individual's IL6 genotype may be highly relevant in other conditions where IL6 has been implicated, such as atherosclerosis.
Adiposity
Qi et al. (2007) studied associations between the genetic variability of IL6 gene and adiposity and long-term changes in 2,255 healthy women and 980 healthy men from 2 prospective cohorts. IL6 haplotype 222211 (possessing rs2069827, rs1800797, rs1800795, rs1554606, rs2069861, and rs1818879; 1 codes the common and 2 codes the minor alleles) was consistently and significantly associated with greater waist circumference (P = 0.009 in men; P = 0.0003 in women) and baseline body mass index (BMI) (P = 0.01 in men; P = 0.046 in women) compared with the most common haplotype 111112. A 5-prime polymorphism, rs2069827, was also consistently associated with significantly higher early-adulthood BMI, baseline BMI, and waist circumference in men and women. The data from this study and a metaanalysis of 26,944 individuals did not support substantial relation between the best-studied IL6 polymorphism, -174G-C (147620.0001), and adiposity.
Kaposi Sarcoma
Foster et al. (2000) found a strong association between the IL6 -174G-C promoter polymorphism (147620.0001) and susceptibility to Kaposi sarcoma (148000) in HIV-infected men. Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with Kaposi sarcoma, whereas allele C homozygotes were underrepresented.
Type 1 Diabetes Mellitus
Kristiansen et al. (2003) genotyped 1,129 individuals from 253 Danish families with insulin-dependent diabetes mellitus (T1D, IDDM; 222100) and found evidence for linkage and association of the IL6 -174G-C SNP (147620.0001) with IDDM, but exclusively in females. IL6 -174CC genotype was associated with younger age at onset in IDDM females. Reporter assays showed that PMA-stimulated promoter activity of the IDDM-predisposing IL6 -174C variant was about 70% higher than the protective IL6 -174G variant in the absence of 17-beta-estradiol (E2). However, the inability of PMA to induce IL6 -174G promoter activity in the absence of E2 was restored by preincubation with E2. Kristiansen et al. (2003) concluded that the IL6 -174C variant-associated risk for IDDM in young females is conferred by high IL6 promoter activity, and that this effect is negated by increasing E2 levels in puberty.
Type 2 Diabetes Mellitus
Mohlig et al. (2004) investigated the IL6 -174C-G SNP (147620.0001) and development of type 2 diabetes mellitus (T2D, NIDDM; 125853). They found that this SNP modified the correlation between BMI and IL6 by showing a much stronger increase of IL6 at increased BMI for CC genotypes compared with GG genotypes. The -174C-G polymorphism was found to be an effect modifier for the impact of BMI regarding NIDDM. The authors concluded that obese individuals with BMI greater than or equal to 28 kg/m2 carrying the CC genotype showed a more than 5-fold increased risk of developing NIDDM compared with the remaining genotypes and, hence, might profit most from weight reduction.
Illig et al. (2004) investigated the association of the IL6 SNPs -174C-G and -598A-G on parameters of type 2 diabetes and the metabolic syndrome in 704 elderly participants of the Kooperative Gesundheitsforschung im Raum Augsburg/Cooperative Research in the Region of Augsburg (KORA) Survey 2000. They found no significant associations, although both SNPs exhibited a positive trend towards association with type 2 diabetes. Illig et al. (2004) also found that circulating IL6 levels were not associated with the IL6 polymorphisms; however, significantly elevated levels of the chemokine monocyte chemoattractant protein-1 (MCP1; 158105)/CC chemokine ligand-2 (CKR2; 601267) in carriers of the protective genotypes suggested an indirect effect of these SNPs on the innate immune system.
Crohn Disease-Associated Growth Failure
Crohn disease (see IBD1, 266600) inhibits growth in up to one-third of affected children. Because IL6 is elevated in Crohn disease, Sawczenko et al. (2005) hypothesized that growth failure would vary with genotype at the IL6 -174 SNP (147620.0001). They found that English and Swedish children with Crohn disease and IL6 -174 GG genotype were more growth retarded at diagnosis and had higher levels of the IL6-induced inflammatory marker C-reactive protein (CRP; 123260) than children with GC or CC genotypes. After corticosteroid or enteral feeding treatment, CRP levels decreased significantly and became comparable to those in children with GC or CC genotypes. Sawczenko et al. (2005) concluded that IL6 -174 genotype mediates growth failure in Crohn disease.
Intracranial Hemorrhage in Brain Arteriovenous Malformations
Among 180 patients with brain arteriovenous malformations (BAVM; 108010), Pawlikowska et al. (2004) found an association between homozygosity for the G allele of the IL6 -174 SNP (147620.0001) and greater risk of intracranial hemorrhage compared to carriers of the C allele (odds ratio of 2.62). In brain tissue from patients with BAVM, Chen et al. (2006) found that the highest IL6 protein and mRNA levels were associated with the IL6 -174GG genotype compared to the GC and CC genotypes. IL6 protein levels were increased in BAVM tissue from patients with hemorrhagic presentation compared to those without hemorrhage. In vivo studies demonstrated that IL6 enhanced expression and activity of IL1B (147720), TNFA (191160), IL8 (146930), and several matrix metalloproteinases, MMP3 (185250), MMP9 (120361), and MMP12 (601046). IL6 also increased proliferation and migration of cultured human cerebral endothelial cells. Chen et al. (2006) suggested that IL6 expression may modulate downstream inflammatory and angiogenic targets that contribute to intracranial hemorrhage in BAVMs.
Systemic Lupus Erythematosus
Linker-Israeli et al. (1999) used PCR and RFLP analysis to genotype the AT-rich minisatellite in the 3-prime flanking region and the 5-prime promoter-enhancer of IL6 in systemic lupus erythematosus (SLE; 152700) patients and controls. In both African-Americans and Caucasians, short allele sizes (less than 792 bp) at the 3-prime minisatellite were found exclusively in SLE patients, whereas the 828-bp allele was overrepresented in controls. No association was found between SLE and alleles in the 5-prime region of IL6. Patients homo- or heterozygous for the SLE-associated 3-prime minisatellite alleles secreted higher levels of IL6, had higher percentages of IL6-positive monocytes, and showed significantly enhanced IL6 mRNA stability. Linker-Israeli et al. (1999) concluded that the AT-rich minisatellite in the 3-prime region flanking of IL6 is associated with SLE, possibly by increasing accessibility for transcription factors.
Cressman et al. (1996) reported that mice with targeted disruption of the Il6 gene had impaired liver regeneration characterized by liver necrosis and failure. There was a blunted DNA synthetic response in hepatocytes but not in nonparenchymal liver cells. Cressman et al. (1996) also demonstrated that there was an absence of Stat3 (102582) production, suggesting that Stat3 induction during liver regeneration is strictly mediated by Il6. They reported that treatment of Il6-deficient mice with a single preoperative dose of Il6 returned Stat3 binding, gene expression, and hepatocyte proliferation to near normal.
Stunted growth is a major complication of chronic inflammation and recurrent infections in children. Systemic juvenile rheumatoid arthritis (604302) is a chronic inflammatory disorder characterized by markedly elevated circulating levels of IL6 and stunted growth. An explanation for this association may be provided by the findings of De Benedetti et al. (1997), who demonstrated that transgenic mouse lines carrying the human IL6 gene driven by the rat neurospecific enolase promoter expressed high levels of circulating IL6 from soon after birth and presented a reduced growth rate that led to mice 50 to 70% the size of nontransgenic littermates. Administration of a monoclonal antibody to the murine Il6 receptor partially reverted the growth defect. In the transgenic mice, circulating levels of insulin-like growth factor I (IGF1; 147440) were significantly lower than those of nontransgenic littermates; on the contrary, the distribution of growth hormone pituitary cells, as well as circulating growth hormone levels, were normal. Treatment of nontransgenic mice of the same strain with IL6 resulted in a significant decrease in IGF I levels. In patients with systemic juvenile rheumatoid arthritis, circulating IL6 levels were negatively correlated with IGF I levels. The findings suggested that IL6-mediated decrease in IGF I production is a major mechanism by which chronic inflammation affects growth.
Using a turpentine-induced model of subacute inflammation in mice null for the gene encoding corticotropin-releasing hormone (CRH; 122560), Venihaki et al. (2001) demonstrated that during inflammation Crh is required for a normal adrenocorticotropin hormone (ACTH) increase but not for adrenal corticosterone rise. A paradoxical increase of plasma Il6 associated with Crh deficiency suggested that regulation of Il6 release during inflammation is Crh dependent. Venihaki et al. (2001) also demonstrated that adrenal Il6 expression is Crh dependent, as its basal and inflammation-induced expression was blocked by Crh deficiency. Mice deficient in both Crh and Il6 had a flat hypothalamic-pituitary-adrenal (HPA) response to inflammation.
A subset of plasmacytoma (PCT), designated extramedullary PCT, is distinguished from multiple myeloma and solitary PCT of bone by its distribution among various tissue sites but not bone marrow. Extramedullary (extraosseous) PCTs are rare spontaneous neoplasms of mice but are readily induced in a susceptible mouse strain, BALB/c, by treatment with pristane. The tumors develop in peritoneal granulomas and are characterized by Myc-activating t(12;15) chromosomal translocations and, most frequently, by secretion of IgA. To test directly the contribution of IL6 to PCT development, Kovalchuk et al. (2002) generated BALB/c mice carrying a widely expressed IL6 transgene. All mice exhibited lymphoproliferation and plasmacytosis. By 18 months of age, more than half developed readily transplantable PCTs in lymph nodes, Peyer patches, and sometimes spleen. These neoplasms also had the t(12;15) translocations, but remarkably, none expressed IgA. Approximately 30% of the mice developed follicular and diffuse large cell B-cell lymphomas that often coexisted with PCTs. These findings provided a unique model of extramedullary PCT for studies on pathogenesis and treatment and suggested a role for IL6 in the genesis of germinal center-derived lymphomas.
McLoughlin et al. (2005) showed that Il6 -/- mice with Staphylococcus epidermidis-induced peritoneal inflammation exhibited impaired T-cell recruitment with reduced expression of chemokine receptors (e.g., CCR5; 601373) and defective expression of chemokines (e.g., CCL4; 182284). Experiments with knockin mice expressing mutated forms of gp130 indicated that Il6-mediated T-cell recruitment required gp130-dependent Stat3 activation. McLoughlin et al. (2005) concluded that IL6- and soluble IL6R-mediated signaling influences the nature and retention of the inflammatory infiltrate within inflamed tissue by controlling inflammatory chemokines and apoptotic regulators.
Crohn disease (IBD1; 266600) inhibits growth in up to one-third of affected children. Sawczenko et al. (2005) hypothesized that IL6, induced by intestinal inflammation, retards growth and suppresses IGF1. They treated rats with trinitrobenzenesulfonic acid-induced colitis with anti-IL6 and found that nutrient intake and inflammation did not decrease, but linear growth was restored and plasma and hepatic Igf1 levels increased.
Janssen et al. (2005) found that recombinant human IL6 caused ventilatory and peripheral skeletal muscle atrophy in rats, even after short-term administration. Blood flow redistribution, resulting from IL6-induced myocardial failure, likely caused this muscle atrophy, because IL6 did not exert any direct effect on the diaphragm.
Naugler et al. (2007) noted that hepatocellular carcinoma (HCC; 114550) occurs mainly in men and male mice in models of HCC and is accompanied by increases in serum IL6 and secretion of IL6 by Kupffer cells. They found that all male mice, but only 13% of female mice, developed HCC in response to a chemical carcinogen. However, male Il6 -/- mice resisted HCC, displayed reduced hepatic injury, and survived as well as wildtype or Il6 -/- female mice. Estradiol administration reduced Il6 and HCC in males, and ovariectomy increased Il6 and HCC in females. The protective effect of estradiol was dependent on estrogen receptor-1 (ESR1; 133430). Carcinogen-induced HCC and Il6 production occurred in a Myd88- and Nfkb (see 164011)-dependent manner. Naugler et al. (2007) concluded that estrogens at concentrations present in females, but not in males, suppress IL6 production and therefore inhibit chemically induced liver carcinogenesis. They proposed that estrogen-mimetic compounds capable of inhibiting excessive IL6 production may prevent progression of chronic liver disease to HCC in men. In a commentary, Lawrence et al. (2007) suggested that anti-IL6, which is already used for other conditions, may be an alternative.
Korn et al. (2007) showed that Il6-deficient mice do not develop a T(H)17 response, and their peripheral repertoire is dominated by Foxp3+ (300292) T regulatory cells. However, deletion of T regulatory cells led to the reappearance of T(H)17 cells in Il6-null mice, suggesting an additional pathway by which T(H)17 might be generated in vivo. Korn et al. (2007) showed that an IL2 cytokine family member, IL21 (605384), cooperates with TGF-beta (190180) to induce T(H)17 cells in naive Il6-null T cells and that IL21-receptor-deficient T cells are defective in generating a T(H)17 response.
McFarland-Mancini et al. (2010) noted that IL6 is essential for timely wound healing. Unexpectedly, they found that Il6r-alpha-deficient mice showed no delay in wound healing, although they shared many inflammatory deficits with Il6-deficient mice. Mice lacking both Il6 and Il6r-alpha, or mice lacking Il6 and treated with antibody to Il6r-alpha, exhibited improved wound healing, in terms of macrophage infiltration, fibrin clearance, and wound contraction, compared with Il6-deficient mice. Il6r-alpha-deficient mice appeared to have aberrant MAP kinase activation, which may have contributed to improved healing.
Kane et al. (2011) demonstrated that transmission of the retrovirus mouse mammary tumor virus (MMTV) required commensal intestinal microbiota and that MMTV was bound to LPS. Mice lacking Tlr4, Il6, Il10, or Cd14 (158120), but not those lacking Tlr2 (603028), eliminated MMTV in successive generations. Kane et al. (2011) concluded that LPS-induced TLR4 signaling drives a viral 'subversion' pathway via IL6-dependent IL10 production that promotes viral transmission to successive generations.
Fishman et al. (1998) identified a polymorphism in the 5-prime region of the IL6 gene; at position -174, the frequency of an allele carrying C at this position was approximately 40% and the frequency of an allele carrying a G was approximately 60% in healthy individuals. In 92 patients with systemic-onset juvenile rheumatoid arthritis (604302), the statistically lower frequency of the GC genotype was found. Fishman et al. (1998) demonstrated lower expression of a construct containing the -174C change than was found with the 174G construct. Furthermore, expression from the -174C construct did not change after stimulation by LPS or IL1, whereas increases were observed with -174G. A reduced frequency of the potentially protective CC genotype in young patients with systemic onset juvenile rheumatoid arthritis was thought to contribute to its pathogenesis.
Foster et al. (2000) found a strong association between this IL6 promoter polymorphism and susceptibility to Kaposi sarcoma (148000) in HIV-infected men. Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with Kaposi sarcoma, whereas allele C homozygotes were underrepresented.
Fernandez-Real et al. (2000) studied if the IL6 gene polymorphism leads to differences in fasting and postglucose load plasma lipids in healthy subjects. Subjects with G at position -174 of the IL6 gene were similar in age, sex, body mass index (BMI), and waist-to-hip ratio in comparison with carriers of the C allele. However, G carriers showed almost twice plasma triglycerides, very low density lipoprotein (VLDL) triglycerides, higher fasting and postglucose load free fatty acids, slightly lower high density lipoprotein (HDL)-2 cholesterol, and similar cholesterol and LDL cholesterol levels than carriers of the C allele. Serum IL6 levels correlated positively with fasting triglycerides, VLDL triglycerides, and postload free fatty acids and negatively with HDL cholesterol. The authors concluded that subjects with the G allele, associated with higher IL6 secretion, are prone to lipid abnormalities.
To evaluate whether genetic variability in the IL6 gene is associated with hyperandrogenism, Villuendas et al. (2002) studied 4 common polymorphisms in the IL6 promoter, including -597G-A (147620.0002) and -174G-C, in 85 hyperandrogenic patients and 25 healthy women. The -597G-A and -174G-C polymorphisms were in linkage disequilibrium and were associated with patient or control status. The -597G and -174G alleles were more frequent in patients either considering subjects homozygous for G alleles separately, or considering subjects homozygous and heterozygous for G alleles as a whole. In healthy women, G alleles at -597 and -174 were associated with statistically significant higher circulating levels of IL6 and basal cortisol, 11-deoxycortisol, and 17-hydroxyprogesterone, and a tendency for higher total T concentrations compared with -597A and -174C alleles. The authors concluded that the -597G-A and -174G-C polymorphisms in IL6 are involved in the pathogenesis of hyperandrogenic disorders.
Ferrari et al. (2003) studied 2 allelic variants in the IL6 promoter, -572 and -174 G-C, that alone and in combination influence IL6 activity in vitro and in vivo. The association of IL6 -572 genotypes and -572/-174 G-G haplotypes with serum C-reactive protein (CRP; 123260), serum and urinary C-terminal cross-linking of type I collagen (see 120150), a marker of bone resorption, and osteocalcin (112260), a marker of bone formation, was investigated in a cohort of healthy postmenopausal women. Among IL6 -572 genotypes, CRP was 37% higher and urinary C-terminal cross-linking of type I collagen was 20% higher in the presence of the C allele, whereas serum osteocalcin was not different. IL6 -572/-174 haplotypes (G/C, G/G, and C/G) were significantly associated with all biochemical markers, and additive effects of the 2 polymorphic loci were found. In addition, there was a trend for lower age-adjusted bone mineral density at the lumbar spine in subjects with fewer IL6 protective alleles.
Kristiansen et al. (2003) genotyped 1,129 individuals from 253 Danish families with type 1 dependent diabetes mellitus (T1D, IDDM; 222100) at the IL6 -174G/C SNP. Gender-conditioned transmission disequilibrium test (TDT) analyses revealed that linkage and association with IDDM were present in females exclusively (p = 0.00065 and p = 0.00024, respectively). Heterogeneity analyses (IDDM vs non-IDDM females) excluded preferential meiotic segregation in females and demonstrated differences in the transmission patterns between female and male IDDM offspring. The -174CC genotype was associated with younger age at onset of IDDM in females (p = 0.002). The impact of 17-beta-estradiol (E2) on the -174G/C variants was investigated by reporter studies. The PMA-stimulated activity of the IDDM risk variant (-174C) exceeded that of the IDDM protective variant (-174G) by approximately 70% in the absence of E2, but not with E2 present. The PMA-stimulated activity of the -174G variant was repressed without E2 present, but was derepressed by addition of E2. In contrast, the PMA-stimulated -174C activity was unaffected by E2, as were the constitutive activities of the -174G/C variants. Kristiansen et al. (2003) concluded that higher IL6 promoter activity may confer risk to IDDM in very young females and that this risk may be negated with increasing age, possibly by the increasing E2 levels in puberty.
Mohlig et al. (2004) investigated the -174C-G polymorphism and development of type 2 diabetes mellitus (T2D, NIDDM; 125853). They found that this polymorphism modified the correlation between BMI and IL6 by showing a much stronger increase of IL6 at increased BMI for CC genotypes compared with GG genotypes. The -174C-G polymorphism was found to be an effect modifier for the impact of BMI regarding NIDDM. The authors concluded that obese individuals with BMI greater than or equal to 28 kg/m2 carrying the CC genotype showed a more than 5-fold increased risk of developing NIDDM compared with the remaining genotypes and, hence, might profit most from weight reduction.
Illig et al. (2004) investigated the association of the IL6 SNPs -174C-G and -598a-G on parameters of type 2 diabetes and the metabolic syndrome in 704 elderly participants of the Kooperative Gesundheitsforschung im Raum Augsburg/Cooperative Research in the Region of Augsburg (KORA) Survey 2000. They found no significant associations, although both SNPs exhibited a positive trend towards association with type 2 diabetes. Illig et al. (2004) also found that circulating IL6 levels were not associated with the IL6 polymorphisms; however, significantly elevated levels of the chemokine monocyte chemoattractant protein-1 (MCP1; 158105)/CC chemokine ligand-2 (CKR2; 601267) in carriers of the protective genotypes suggested an indirect effect of these SNPs on the innate immune system.
Obesity represents an expansion of adipose tissue mass and is closely related to insulin resistance and cardiovascular disease. IL6 is one of several hormonal signals that originate from adipose tissue; adipose tissue accounts for one-third of the circulating levels of IL6. Berthier et al. (2003) studied the association between the -174G/C polymorphism of IL6 and indices of obesity in French Canadian men. The -174G/G homozygotes presented the lowest waist circumference (P less than 0.05).
In a study of 2,255 healthy women and 980 healthy men, as well as in a metaanalysis of 26,944 individuals, Qi et al. (2007) did not find evidence of a substantial relation between the -174G-C polymorphism and adiposity.
Crohn disease (see IBD1, 266600) inhibits growth in up to one-third of affected children. Because IL6 is elevated in Crohn disease, Sawczenko et al. (2005) hypothesized that growth failure would vary with IL6 -174 genotype. They found that English and Swedish children with Crohn disease and the -174 GG genotype were more growth retarded at diagnosis and had higher levels of the IL6-induced inflammatory marker C-reactive protein (CRP; 123260) than children with GC or CC genotypes. After corticosteroid or enteral feeding treatment, CRP levels decreased significantly and became comparable to those in children with GC or CC genotypes. Sawczenko et al. (2005) concluded that IL6 -174 genotype mediates growth failure in Crohn disease.
Among 180 patients with brain arteriovenous malformations (BAVM; 108010), Pawlikowska et al. (2004) found an association between homozygosity for the IL6 -174G allele and greater risk of intracranial hemorrhage compared to carriers of the C allele (odds ratio of 2.62). In brain tissue from patients with BAVM, Chen et al. (2006) found that the highest IL6 protein and mRNA levels were associated with the IL6 -174GG genotype compared to the GC and CC genotypes. IL6 protein levels were increased in BAVM tissue from patients with hemorrhagic presentation compared to those without hemorrhage. In vivo studies demonstrated that IL6 enhanced expression and activity of IL1B (147720), TNFA (191160), IL8 (146930), and several matrix metalloproteinases, MMP3 (185250), MMP9 (120361), and MMP12 (601046). IL6 also increased proliferation and migration of cultured human cerebral endothelial cells. Chen et al. (2006) suggested that IL6 expression may modulate downstream inflammatory and angiogenic targets that contribute to intracranial hemorrhage in BAVMs.
See 147620.0001 and Villuendas et al. (2002).
Ancrile, B., Lim, K.-H., Counter, C. M. Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev. 21: 1714-1719, 2007. [PubMed: 17639077] [Full Text: https://doi.org/10.1101/gad.1549407]
Berthier, M.-T., Paradis, A.-M., Tchernof, A., Bergeron, J., Prud'homme, D., Despres, J.-P., Vohl, M.-C. The interleukin 6 -174G/C polymorphism is associated with indices of obesity in men. J. Hum. Genet. 48: 14-19, 2003. [PubMed: 12560873] [Full Text: https://doi.org/10.1007/s100380300002]
Boulanger, M. J., Chow, D., Brevnova, E. E., Garcia, K. C. Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science 300: 2101-2104, 2003. Note: Erratum: Science 301: 918 only, 2003. [PubMed: 12829785] [Full Text: https://doi.org/10.1126/science.1083901]
Bowcock, A. M., Kidd, J. R., Lathrop, G. M., Daneshvar, L., May, L. T., Ray, A., Sehgal, P. B., Kidd, K. K., Cavalli-Sforza, L. L. The human 'interferon-beta-2/hepatocyte stimulating factor/interleukin-6' gene: DNA polymorphism studies and localization to chromosome 7p21. Genomics 3: 8-16, 1988. [PubMed: 2906047] [Full Text: https://doi.org/10.1016/0888-7543(88)90152-8]
Chen, Y., Ferguson-Smith, A. C., Newman, M. S., May, L. T., Sehgal, P. B., Ruddle, F. H. Regional localization of the human beta 2-interferon gene. (Abstract) Am. J. Hum. Genet. 41: A161, 1987.
Chen, Y., Pawlikowska, L., Yao, J. S., Shen, F., Zhai, W., Achrol, A. S., Lawton, M. T., Kwok, P.-Y., Yang, G.-Y., Young, W. L. Interleukin-6 involvement in brain arteriovenous malformations. Ann. Neurol. 59: 72-80, 2006. [PubMed: 16278864] [Full Text: https://doi.org/10.1002/ana.20697]
Chow, D., He, X., Snow, A. L., Rose-John, S., Garcia, K. C. Structure of an extracellular gp130 cytokine receptor signaling complex. Science 291: 2150-2155, 2001. [PubMed: 11251120] [Full Text: https://doi.org/10.1126/science.1058308]
Chowdhury, S., Schulz, L., Palmisano, B., Singh, P., Berger, J. M., Yadav, V. K., Mera, P., Ellingsgaard, H., Hidalgo, J., Bruning, J., Karsenty, G. Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts. J. Clin. Invest. 130: 2888-2902, 2020. [PubMed: 32078586] [Full Text: https://doi.org/10.1172/JCI133572]
Chung, H. W., Seo, J.-S., Hur, S. E., Kim, H. L., Kim, J. Y., Jung, J. H., Kim, L. H., Park, B. L., Shin, H. D. Association of interleukin-6 promoter variant with bone mineral density in pre-menopausal women. J. Hum. Genet. 48: 243-248, 2003. [PubMed: 12768442] [Full Text: https://doi.org/10.1007/s10038-003-0020-8]
Chung, U., Tanaka, Y., Fujita, T. Association of interleukin-6 and hypoaldosteronism in patients with cancer. (Letter) New Eng. J. Med. 334: 473, 1996. [PubMed: 8552163] [Full Text: https://doi.org/10.1056/NEJM199602153340716]
Cressman, D. E., Greenbaum, L. E., DeAngelis, R. A., Ciliberto, G., Furth, E. E., Poli, V., Taub, R. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274: 1379-1382, 1996. [PubMed: 8910279] [Full Text: https://doi.org/10.1126/science.274.5291.1379]
Dai, J., Miller, A. H., Bremner, J. D., Goldberg, J., Jones, L., Shallenberger, L., Buckham, R., Murrah, N. V., Veledar, E., Wilson, P. W., Vaccarino, V. Adherence to the Mediterranean diet is inversely associated with circulating interleukin-6 among middle-aged men. Circulation 117: 169-175, 2008. [PubMed: 18086924] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.710699]
De Benedetti, F., Alonzi, T., Moretta, A., Lazzaro, D., Costa, P., Poli, V., Martini, A., Ciliberto, G., Fattori, E. Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. J. Clin. Invest. 99: 643-650, 1997. [PubMed: 9045866] [Full Text: https://doi.org/10.1172/JCI119207]
De Groof, F., Joosten, K. F. M., Janssen, J. A. M. J. L., De Kleijn, E. D., Hazelzet, J. A., Hop, W. C. J., Uitterlinden, P., Van Doorn, J., Hokken-Koelega, A. C. S. Acute stress response in children with meningococcal sepsis: important differences in the growth hormone/insulin-like growth factor I axis between nonsurvivors and survivors. J. Clin. Endocr. Metab. 87: 3118-3124, 2002. [PubMed: 12107211] [Full Text: https://doi.org/10.1210/jcem.87.7.8605]
Ellingsgaard, H., Hauselmann, I., Schuler, B., Habib, A. M., Baggio, L. L., Meier, D. T., Eppler, E., Bouzakri, K., Wueest, S., Muller, Y. D., Hansen, A. M. K., Reineke, M., and 9 others. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nature Med. 17: 1481-1489, 2011. [PubMed: 22037645] [Full Text: https://doi.org/10.1038/nm.2513]
Fairfax, B. P., Vannberg, F. O., Radhakrishnan, J., Hakonarson, H., Keating, B. J., Hill, A. V. S., Knight, J. C. An integrated expression phenotype mapping approach defines common variants in LEP, ALOX15 and CAPNS1 associated with induction of IL-6. Hum. Molec. Genet. 19: 720-730, 2010. [PubMed: 19942621] [Full Text: https://doi.org/10.1093/hmg/ddp530]
Ferguson-Smith, A. C., Chen, Y.-F., Newman, M. S., May, L. T., Sehgal, P. B., Ruddle, F. H. Regional localization of the interferon beta-2/B-cell stimulatory factor 2/hepatocyte stimulating factor gene to human chromosome 7p15-p21. Genomics 2: 203-208, 1988. [PubMed: 3294161] [Full Text: https://doi.org/10.1016/0888-7543(88)90003-1]
Fernandez-Real, J.-M., Broch, M., Vendrell, J., Richart, C., Ricart, W. Interleukin-6 gene polymorphism and lipid abnormalities in healthy subjects. J. Clin. Endocr. Metab. 85: 1334-1339, 2000. [PubMed: 10720087] [Full Text: https://doi.org/10.1210/jcem.85.3.6555]
Ferrari, S. L., Ahn-Luong, L., Garnero, P., Humphries, S. E., Greenspan, S. L. Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women. J. Clin. Endocr. Metab. 88: 255-259, 2003. [PubMed: 12519862] [Full Text: https://doi.org/10.1210/jc.2002-020092]
Fishman, D., Faulds, G., Jeffery, R., Mohamed-Ali, V., Yudkin, J. S., Humphries, S., Woo, P. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J. Clin. Invest. 102: 1369-1376, 1998. [PubMed: 9769329] [Full Text: https://doi.org/10.1172/JCI2629]
Foster, C. B., Lehrnbecher, T., Samuels, S., Stein, S., Mol, F., Metcalf, J. A., Wyvill, K., Steinberg, S. M., Kovacs, J., Blauvelt, A., Yarchoan, R., Chanock, S. J. An IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in men infected with human immunodeficiency virus. Blood 96: 2562-2567, 2000. [PubMed: 11001912]
Funatsu, H., Yamashita, H., Noma, H., Mimura, T., Yamashita, T., Hori, S. Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am. J. Ophthal. 133: 70-77, 2002. [PubMed: 11755841] [Full Text: https://doi.org/10.1016/s0002-9394(01)01269-7]
Ghoreschi, K., Laurence, A., Yang, X.-P., Tato, C. M., McGeachy, M. J., Konkel, J. E., Ramos, H. L., Wei, L., Davidson, T. S., Bouladoux, N., Grainger, J. R., Chen, Q., and 9 others. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467: 967-971, 2010. [PubMed: 20962846] [Full Text: https://doi.org/10.1038/nature09447]
Harker, J. A., Lewis, G. M., Mack, L., Zuniga, E. I. Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. Science 334: 825-829, 2011. [PubMed: 21960530] [Full Text: https://doi.org/10.1126/science.1208421]
Hirano, T., Yasukawa, K., Harada, H., Taga, T., Watanabe, Y., Matsuda, T., Kashiwamura, S., Nakajima, K., Koyama, K., Iwamatsu, A., Tsunasawa, S., Sakiyama, F., Matsui, H., Takahara, Y., Taniguchi, T., Kishimoto, T. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324: 73-76, 1986. [PubMed: 3491322] [Full Text: https://doi.org/10.1038/324073a0]
Illig, T., Bongardt, F., Schopfer, A., Muller-Scholze, S., Rathmann, W., Koenig, W., Thorand, B., Vollmert, C., Holle, R., Kolb, H., Herder, C., Members of the Kooperative Gesundheitsforschung im Raum Augsburg/Cooperative Research in the Region of Augsburg (KORA). Significant association of the interleukin-6 gene polymorphisms C-174G and A-598G with type 2 diabetes. J. Clin. Endocr. Metab. 89: 5053-5058, 2004. Note: Erratum: J. Clin. Endocr. Metab. 90: 6385 only, 2005. [PubMed: 15472205] [Full Text: https://doi.org/10.1210/jc.2004-0355]
Janssen, S. P. M., Gayan-Ramirez, G., Van Den Bergh, A., Herijgers, P., Maes, K., Verbeken, E., Decramer, M. Interleukin-6 causes myocardial failure and skeletal muscle atrophy in rats. Circulation 111: 996-1005, 2005. [PubMed: 15710765] [Full Text: https://doi.org/10.1161/01.CIR.0000156469.96135.0D]
Kane, M., Case, L. K., Kopaskie, K., Kozlova, A., MacDearmid, C., Chervonsky, A. V., Golovkina, T. V. Successful transmission of a retrovirus depends on the commensal microbiota. Science 334: 245-249, 2011. [PubMed: 21998394] [Full Text: https://doi.org/10.1126/science.1210718]
Kawano, M., Hirano, T., Matsuda, T., Taga, T., Horii, Y., Iwato, K., Asaoku, H., Tang, B., Tanabe, O., Tanaka, H., Kuramoto, A., Kishimoto, T. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332: 83-85, 1988. [PubMed: 3258060] [Full Text: https://doi.org/10.1038/332083a0]
Kiecolt-Glaser, J. K., Preacher, K. J., MacCullum, R. C., Atkinson, C., Malarkey, W. B., Glaser, R. Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc. Nat. Acad. Sci. 100: 9090-9095, 2003. [PubMed: 12840146] [Full Text: https://doi.org/10.1073/pnas.1531903100]
Korn, T., Bettelli, E., Gao, W., Awasthi, A., Jager, A., Strom, T. B., Oukka, M., Kuchroo, V. K. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448: 484-487, 2007. [PubMed: 17581588] [Full Text: https://doi.org/10.1038/nature05970]
Kovalchuk, A. L., Kim, J. S., Park, S. S., Coleman, A. E., Ward, J. M., Morse, H. C, III, Kishimoto, T., Potter, M., Janz, S. IL-6 transgenic mouse model for extraosseous plasmacytoma. Proc. Nat. Acad. Sci. 99: 1509-1514, 2002. [PubMed: 11805288] [Full Text: https://doi.org/10.1073/pnas.022643999]
Kristiansen, O. P., Nolsoe, R. L., Larsen, L., Gjesing, A. M. P., Johannesen, J., Larsen, Z. M., Lykkesfeldt, A. E., Karlsen, A. E., Pociot, F., Mandrup-Poulsen, T. Association of a functional 17-beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females. Hum. Molec. Genet. 12: 1101-1110, 2003. [PubMed: 12719374] [Full Text: https://doi.org/10.1093/hmg/ddg132]
Lawrence, T., Hagemann, T., Balkwill, F. Sex, cytokines, and cancer. Science 317: 51-52, 2007. [PubMed: 17615328] [Full Text: https://doi.org/10.1126/science.1146052]
Linker-Israeli, M., Wallace, D. J., Prehn, J., Michael, D., Honda, M., Taylor, K. D., Paul-Labrador, M., Fischel-Ghodsian, N., Fraser, P. A., Klinenberg, J. R. Association of IL-6 gene alleles with systemic lupus erythematosus (SLE) and with elevated IL-6 expression. Genes Immun. 1: 45-52, 1999. [PubMed: 11197305] [Full Text: https://doi.org/10.1038/sj.gene.6363631]
Liuzzi, J. P., Lichten, L. A., Rivera, S., Blanchard, R. K., Aydemir, T. B., Knutson, M. D., Ganz, T., Cousins, R. J. Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response. Proc. Nat. Acad. Sci. 102: 6843-6848, 2005. [PubMed: 15863613] [Full Text: https://doi.org/10.1073/pnas.0502257102]
May, L. T., Ghrayeb, J., Santhanam, U., Tatter, S. B., Sthoeger, Z., Helfgott, D. C., Chiorazzi, N., Grieninger, G., Sehgal, P. B. Synthesis and secretion of multiple forms of beta-2-interferon/B-cell differentiation factor 2/hepatocyte-stimulating factor by human fibroblasts and monocytes. J. Biol. Chem. 263: 7760-7766, 1988. [PubMed: 3131326]
McFarland-Mancini, M. M., Funk, H. M., Paluch, A. M., Zhou, M., Giridhar, P. V., Mercer, C. A., Kozma, S. C., Drew, A. F. Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J. Immun. 184: 7219-7228, 2010. [PubMed: 20483735] [Full Text: https://doi.org/10.4049/jimmunol.0901929]
McLoughlin, R. M., Jenkins, B. J., Grail, D., Williams, A. S., Fielding, C. A., Parker, C. R., Ernst, M., Topley, N., Jones, S. A. IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proc. Nat. Acad. Sci. 102: 9589-9594, 2005. [PubMed: 15976028] [Full Text: https://doi.org/10.1073/pnas.0501794102]
Meng, F., Wehbe-Janek, H., Henson, R., Smith, H., Patel, T. Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes. Oncogene 27: 378-386, 2008. [PubMed: 17621267] [Full Text: https://doi.org/10.1038/sj.onc.1210648]
Mohlig, M., Boeing, H., Spranger, J., Osterhoff, M., Kroke, A., Fisher, E., Bergmann, M. M., Ristow, M., Hoffmann, K., Pfeiffer, A. F. H. Body mass index and C-174G interleukin-6 promoter polymorphism interact in predicting type 2 diabetes. J. Clin. Endocr. Metab. 89: 1885-1890, 2004. [PubMed: 15070960] [Full Text: https://doi.org/10.1210/jc.2003-031101]
Mora, J. R., Iwata, M., Eksteen, B., Song, S.-Y., Junt, T., Senman, B., Otipoby, K. L., Yokota, A., Takeuchi, H., Ricciardi-Castagnoli, P., Rajewsky, K., Adams, D. H., von Andrian, U. H. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314: 1157-1160, 2006. [PubMed: 17110582] [Full Text: https://doi.org/10.1126/science.1132742]
Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., Cheroutre, H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256-260, 2007. [PubMed: 17569825] [Full Text: https://doi.org/10.1126/science.1145697]
Naugler, W. E., Sakurai, T., Kim, S., Maeda, S., Kim, K., Elsharkawy, A. M., Karin, M. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317: 121-124, 2007. Note: Erratum: Science 326: 1346 only, 2009. [PubMed: 17615358] [Full Text: https://doi.org/10.1126/science.1140485]
Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., Ganz, T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113: 1271-1276, 2004. [PubMed: 15124018] [Full Text: https://doi.org/10.1172/JCI20945]
Ota, N., Hunt, S. C., Nakajima, T., Suzuki, T., Hosoi, T., Orimo, H., Shirai, Y., Emi, M. Linkage of interleukin 6 locus to human osteopenia by sibling pair analysis. Hum. Genet. 105: 253-257, 1999. [PubMed: 10987653] [Full Text: https://doi.org/10.1007/s004390051097]
Ota, N., Nakajima, T., Nakazawa, I., Suzuki, T., Hosoi, T., Orimo, H., Inoue, S., Shirai, Y., Emi, M. A nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density. J. Hum. Genet. 46: 267-272, 2001. [PubMed: 11355017] [Full Text: https://doi.org/10.1007/s100380170077]
Pasare, C., Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299: 1033-1036, 2003. [PubMed: 12532024] [Full Text: https://doi.org/10.1126/science.1078231]
Pawlikowska, L., Tran, M. N., Achrol, A. S., McCulloch, C. E., Ha, C., Lind, D. L., Hashimoto, T., Zaroff, J., Lawton, M. T., Marchuk, D. A., Kwok, P.-Y., Young, W. L., UCSF BAVM Study Project. Polymorphisms in genes involved in inflammatory and angiogenic pathways and the risk of hemorrhagic presentation of brain arteriovenous malformations. Stroke 35: 2294-2299, 2004. [PubMed: 15331795] [Full Text: https://doi.org/10.1161/01.STR.0000141932.44613.b1]
Powrie, F., Maloy, K. J. Regulating the regulators. Science 299: 1030-1031, 2003. [PubMed: 12586934] [Full Text: https://doi.org/10.1126/science.1082031]
Qi, L., Zhang, C., van Dam, R. M., Hu, F. B. Interleukin-6 genetic variability and adiposity: associations in two prospective cohorts and systematic review in 26,944 individuals. J. Clin. Endocr. Metab. 92: 3618-3625, 2007. [PubMed: 17623760] [Full Text: https://doi.org/10.1210/jc.2007-0877]
Redwine, L., Hauger, R. L., Gillin, J. C., Irwin, M. Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans. J. Clin. Endocr. Metab. 85: 3597-3603, 2000. [PubMed: 11061508] [Full Text: https://doi.org/10.1210/jcem.85.10.6871]
Roodman, G. D., Kurihara, N., Ohsaki, Y., Kukita, A., Hosking, D., Demulder, A., Smith, J. F., Singer, F. R. Interleukin 6: a potential autocrine/paracrine factor in Paget's disease of bone. J. Clin. Invest. 89: 46-52, 1992. [PubMed: 1729280] [Full Text: https://doi.org/10.1172/JCI115584]
Rooney, M., David, J., Symons, J., Di Giovine, F., Varsani, H., Woo, P. Inflammatory cytokine responses in juvenile chronic arthritis. Brit. J. Rheum. 34: 454-460, 1995. [PubMed: 7788176] [Full Text: https://doi.org/10.1093/rheumatology/34.5.454]
Sabio, G., Das, M., Mora, A., Zhang, Z., Jun, J. Y., Ko, H. J., Barrett, T., Kim, J. K., Davis, R. J. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322: 1539-1543, 2008. [PubMed: 19056984] [Full Text: https://doi.org/10.1126/science.1160794]
Santhanam, U., Ray, A., Sehgal, P. B. Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. Proc. Nat. Acad. Sci. 88: 7605-7609, 1991. [PubMed: 1652755] [Full Text: https://doi.org/10.1073/pnas.88.17.7605]
Sawczenko, A., Azooz, O., Paraszczuk, J., Idestrom, M., Croft, N. M., Savage, M. O., Ballinger, A. B., Sanderson, I. R. Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the -174 IL-6 G/C polymorphism in children. Proc. Nat. Acad. Sci. 102: 13260-13265, 2005. [PubMed: 16150725] [Full Text: https://doi.org/10.1073/pnas.0503589102]
Scheidt-Nave, C., Bismar, H., Leidig-Bruckner, G., Woitge, H., Seibel, M. J., Ziegler, R., Pfeilschifter, J. Serum interleukin 6 is a major predictor of bone loss in women specific to the first decade past menopause. J. Clin. Endocr. Metab. 86: 2032-2042, 2001. [PubMed: 11344203] [Full Text: https://doi.org/10.1210/jcem.86.5.7445]
Seddon, J. M., George, S., Rosner, B., Fifai, N. Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers. Arch. Ophthal. 123: 774-782, 2005. [PubMed: 15955978] [Full Text: https://doi.org/10.1001/archopht.123.6.774]
Sehgal, P. B., May, L. T., Tamm, I., Vilcek, J. Human beta-2 interferon and B-cell differentiation factor BSF-2 are identical. Science 235: 731-732, 1987. [PubMed: 3492764] [Full Text: https://doi.org/10.1126/science.3492764]
Sehgal, P. B., Walther, Z., Tamm, I. Rapid enhancement of beta(2)-interferon/B-cell differentiation factor BSF-2 gene expression in human fibroblasts by diacylglycerols and the calcium ionophore A23187. Proc. Nat. Acad. Sci. 84: 3663-3667, 1987. [PubMed: 3108877] [Full Text: https://doi.org/10.1073/pnas.84.11.3663]
Sehgal, P. B., Zilberstein, A., Ruggieri, R.-M., May, L. T., Ferguson-Smith, A., Slate, D. L., Revel, M., Ruddle, F. H. Human chromosome 7 carries the beta-2 interferon gene. Proc. Nat. Acad. Sci. 83: 5219-5222, 1986. [PubMed: 3014537] [Full Text: https://doi.org/10.1073/pnas.83.14.5219]
Suthaus, J., Stuhlmann-Laeisz, C., Tompkins, V. S., Rosean, T. R., Klapper, W., Tosato, G., Janz, S., Scheller, J., Rose-John, S. HHV8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice. Blood 119: 5173-5181, 2012. [PubMed: 22490805] [Full Text: https://doi.org/10.1182/blood-2011-09-377705]
Sutherland, G. R., Baker, E., Callen, D. F., Hyland, V. J., Wong, G., Clark, S., Jones, S. S., Eglinton, L. K., Shannon, M. F., Lopez, A. F., Vadas, M. A. Interleukin 4 is at 5q31 and interleukin 6 is at 7p15. Hum. Genet. 79: 335-337, 1988. [PubMed: 3261707] [Full Text: https://doi.org/10.1007/BF00282171]
Tosato, G., Seamon, K. B., Goldman, N. D., Sehgal, P. B., May, L. T., Washington, G. C., Jones, K. D., Pike, S. E. Monocyte-derived human B-cell growth factor identified as interferon-beta-2 (BSF-2, IL-6). Science 239: 502-504, 1988. [PubMed: 2829354] [Full Text: https://doi.org/10.1126/science.2829354]
Venihaki, M., Dikkes, P., Carrigan, A., Karalis, K. P. Corticotropin-releasing hormone regulates IL-6 expression during inflammation. J. Clin. Invest. 108: 1159-1166, 2001. [PubMed: 11602623] [Full Text: https://doi.org/10.1172/JCI12869]
Viereck, V., Grundker, C., Blaschke, S., Niederkleine, B., Siggelkow, H., Frosch, K.-H., Raddatz, D., Emons, G., Hofbauer, L. C. Raloxifene concurrently stimulates osteoprotegerin and inhibits interleukin-6 production by human trabecular osteoblasts. J. Clin. Endocr. Metab. 88: 4206-4213, 2003. [PubMed: 12970288] [Full Text: https://doi.org/10.1210/jc.2002-021877]
Villuendas, G., San Millan, J. L., Sancho, J., Escobar-Morreale, H. F. The -597 G-A and -174 G-C polymorphisms in the promoter of the IL-6 gene are associated with hyperandrogenism. J. Clin. Endocr. Metab. 87: 1134-1141, 2002. [PubMed: 11889177] [Full Text: https://doi.org/10.1210/jcem.87.3.8309]
Weissenbach, J., Chernajovsky, Y., Zeevi, M., Shulman, L., Soreq, H., Nir, U., Wallach, D., Perricaudet, M., Tiollais, P., Revel, M. Two interferon mRNAs in human fibroblasts: in vitro translation and Escherichia coli cloning studies. Proc. Nat. Acad. Sci. 77: 7152-7156, 1980. [PubMed: 6164058] [Full Text: https://doi.org/10.1073/pnas.77.12.7152]
Xu, Z., Xiao, S.-B., Xu, P., Xie, Q., Cao, L., Wang, D., Luo, R., Zhong, Y., Chen, H.-C., Fang, L.-R. miR-365, a novel negative regulator of interleukin-6 gene expression, is cooperatively regulated by Sp1 and NK-kappa-B. J. Biol. Chem. 286: 21401-21412, 2011. [PubMed: 21518763] [Full Text: https://doi.org/10.1074/jbc.M110.198630]
Zenker, S., Panteleev-Ivlev, J., Wirtz, S., Kishimoto, T., Waldner, M. J., Ksionda, O., Tybulewicz, V. L. J., Neurath, M. F., Atreya, I. A key regulatory role for Vav1 in controlling lipopolysaccharide endotoxemia via macrophage-derived IL-6. J. Immun. 192: 2830-2836, 2014. [PubMed: 24532586] [Full Text: https://doi.org/10.4049/jimmunol.1300157]
Zhang, C., Xin, H., Zhang, W., Yazaki, P. J., Zhang, Z., Le, K., Li, W., Lee, H., Kwak, L., Forman, S., Jove, R., Yu, H. CD5 binds to interleukin-6 and induces a feed-forward loop with the transcription factor STAT3 in B cells to promote cancer. Immunity 44: 913-923, 2016. [PubMed: 27096320] [Full Text: https://doi.org/10.1016/j.immuni.2016.04.003]
Zhang, Q., Zhao, K., Shen, Q., Han, Y., Gu, Y., Li, X., Zhao, D., Liu, Y., Wang, C., Zhang, X., Su, X., Liu, J., Ge, W., Levine, R. L., Li, N., Cao, X. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525: 389-393, 2015. [PubMed: 26287468] [Full Text: https://doi.org/10.1038/nature15252]
Zilberstein, A., Ruggieri, R., Korn, J. H., Revel, M. Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines. EMBO J. 5: 2529-2537, 1986. [PubMed: 3023045] [Full Text: https://doi.org/10.1002/j.1460-2075.1986.tb04531.x]