Alternative titles; symbols
HGNC Approved Gene Symbol: IL1A
Cytogenetic location: 2q14.1 Genomic coordinates (GRCh38): 2:112,773,925-112,784,493 (from NCBI)
IL1A is 1 of 2 structurally distinct forms of IL1, the other being IL1B (147720). The IL1A and IL1B proteins are synthesized by a variety of cell types, including activated macrophages, keratinocytes, stimulated B lymphocytes, and fibroblasts, and are potent mediators of inflammation and immunity (Lord et al., 1991).
From the mRNA of lipopolysaccharide (LPS)-stimulated macrophages, March et al. (1985) isolated 2 distinct cDNAs encoding proteins with characteristic IL1 activity, defined by the induction of IL2 (147680) synthesis by a T-cell line or by thymocytes. They termed the proteins IL1-alpha and IL1-beta. The primary IL1-alpha and IL1-beta translation products contain 271 and 269 amino acids, respectively. They have deduced molecular masses of 30.6 and 30.7 kD, respectively. IL1-alpha and IL1-beta share only 26% homology at the protein level and 45% homology at the nucleic acid level. Furutani et al. (1986) noted that IL1A is acidic, whereas IL1B is neutral.
Furutani et al. (1986) determined that the IL1A gene spans 10.2 kb and has 7 exons.
By Southern transfer analysis of DNAs from human-rodent somatic cell hybrids, Modi et al. (1988) assigned the IL1A gene to chromosome 2. Regional localization to chromosome 2q13-q21 was achieved by in situ hybridization. Lafage et al. (1989) confirmed assignment to chromosome 2q13 by in situ hybridization.
From restriction mapping of the human genomic region, Nicklin et al. (1994) found that, relative to 1 terminal CpG island, the IL1A, IL1B, and IL1RN (147679) genes mapped to the following intervals: IL1A was between +0 and +35 kb, IL1B was between +70 and +110 kb, and IL1RN was between +330 and +430 kb. Since the assignment of IL1RN to chromosome 2q14.2 appears to be the most definitive localization, the IL1A and IL1B genes can be presumably be said to be also on chromosome 2q14.
Boultwood et al. (1989) used in situ chromosome hybridization to show that the 2 Il1 genes in the mouse are located in the F region of chromosome 2. It had previously been shown by studies in mouse-hamster somatic cell hybrids and in recombinant inbred strains that the 2 genes are tightly linked on murine chromosome 2, approximately 4.7 cM distal to beta-2-microglobulin. By pulsed field gel electrophoresis, Silver et al. (1990) showed that the mouse Il1a and Il1b genes are contained in a genomic fragment of about 70 kb. Further studies suggested that Il1b lies 5-prime to Il1a, that the 2 genes are oriented in the same direction, and that they are separated by about 50 kb.
Nicklin et al. (2002) determined that the gene order within the IL1 gene cluster on chromosome 2, from centromere to telomere, is IL1A-IL1B-IL1F7 (IL37; 605510)-IL1F9 (IL36G; 605542)-IL1F6 (IL36A; 605509)-IL1F8 (IL36B; 605508)-IL1F5 (IL36RN; 605507)-IL1F10 (615296)-IL1RN. Of these, only IL1A, IL1B, and IL36B are transcribed toward the centromere.
March et al. (1985) found that expression of the C-terminal 159 and 153 amino acids of human IL1-alpha and IL1-beta in E. coli produced IL1 biologic activity. Thus, IL1-alpha and IL1-beta appear to be synthesized as large precursors that are processed to smaller forms.
Cannon and Dinarello (1985) developed a method for studying IL1 levels in plasma samples from febrile patients. They also consistently found IL1 activity in women in the luteal phase of their menstrual cycle, whereas it was low in healthy men and preovulatory women. The increase in IL1 during the luteal phase of the menstrual cycle was consistent with the 0.2 to 0.6 degree Celsius rise in body temperature that occurs at that time, and appeared to be associated with an upward shift in the thermoregulatory set point, as occurs with fever. Cannon and Dinarello (1985) concluded that IL1 appears to have a role in normal physiologic conditions as well as in disease states.
Both IL1-alpha and IL1-beta are initially translated as approximately 30-kD polypeptides that are processed to approximately 17.5-kD polypeptides prior to, or during, release from macrophages. Using an in vitro transcription-translation system to produce these 4 forms of IL1 directly from cloned cDNAs, Mosley et al. (1987) showed that the initial translation product from IL1-beta mRNA had to be processed to bind to IL1 receptor (IL1R; 147810) and express biologic activity. In contrast, the initial translation product of IL1-alpha mRNA could bind to IL1R without further proteolytic processing. Mosley et al. (1987) concluded that the IL1 biologic activity associated with proteins having molecular masses in the range of 30 to 40 kD is due to IL1-alpha gene products.
Lord et al. (1991) demonstrated that both the alpha and beta forms of IL1, but particularly the beta form, were transcribed in polymorphonuclear leukocytes stimulated with LPS. Both IL1A and IL1B stimulated osteoclast activity in vitro and were potent bone resorbing factors.
Sabatini et al. (1988) studied the effects of 72-hour subcutaneous infusions of IL1-alpha and -beta on plasma, calcium, and bone morphology. Both proteins caused a marked, dose-dependent increase in plasma calcium. Increased numbers of osteoclasts and bone resorption surfaces were observed on quantitative histomorphometry of bone. The results suggest a role for IL1 in the modulation of extracellular fluid calcium homeostasis.
Hogquist et al. (1991) demonstrated that IL1 is involved in apoptosis. Both the alpha and the beta forms were released as a consequence of cell injury, regardless of the insult.
Hurwitz et al. (1992) studied the role of IL1 in the ovary, using a solution hybridization/RNase protection assay to test for expression of the IL1 gene, its type I receptor (IL1R), and its receptor antagonist (IL1RN). They presented findings which, taken together, revealed the existence of a complete, highly compartmentalized, hormone-dependent intraovarian IL1 system.
Werman et al. (2004) overexpressed the precursor form of IL1A in different cell types in the presence of saturating concentrations of IL1RN. Using fluorescent microscopy, they observed that the precursor was initially present in the cytoplasm of resting cells, then translocated to the nucleus after activation by endotoxin, a TLR (see TLR4; 603030) ligand. The IL1A precursor or its propiece, but not the C-terminal mature form, activated a GAL4 transcription system, probably through the N terminus where the nuclear localization signal resides. Overexpressed precursor and propiece forms were also sufficient to activate NFKB (164011) and AP1 (165160). Stable transfected cell lines overproducing IL1A released IL8 (146930) and IL6 and exhibited a low threshold of activation to very low concentrations of TNF. Werman et al. (2004) suggested that the intracellular functions of IL1A may play a role in the genesis of inflammation by augmenting the transcription of proinflammatory genes, a mechanism not affected by extracellular inhibitors.
In studies of the effect of statin drugs on IL1A, IL1B, and IL1RN levels in individuals with and without coronary artery disease (CAD), Waehre et al. (2004) found that IL1A and IL1B mRNA levels were markedly reduced in peripheral blood mononuclear cells (PBMCs) from CAD patients after 6 months of statin therapy, with a lesser reduction in IL1RN. IL1A, IL1B, and IL1RN mRNA levels were increased in patients with stable and unstable angina compared to controls; particularly high levels of IL1A and IL1B were seen in the unstable patients, who did not, however, have correspondingly high IL1RN levels, suggesting a net inflammatory dominance in those patients. IL1B induced the release of proatherogenic cytokines from PBMCs, whereas atorvastatin partly abolished that effect.
TNF-induced RANKL (TNFSF11; 602642) synthesis by bone marrow stromal cells is a fundamental component of inflammatory osteolysis. Wei et al. (2005) found that TNF-induced RANKL expression in murine stromal cells was mediated by IL1 via enhanced expression of IL1R1. IL1 had the capacity to directly target mononuclear osteoclast precursors and promote their differentiation in the presence of sufficient RANKL. Wei et al. (2005) concluded that IL1 is a key downstream effector molecule in optimal TNF-induced osteoclastogenesis, participating in the stimulation of stromal cell RANKL expression and in the stimulation of osteoclast precursor differentiation.
Mesenchymal stem cells (MSCs) primarily reside in adult bone marrow and can generate functional neuronal cells. Human MSC-derived neuronal cells express the TAC1 (162320) transcript, but not its peptide product, substance P, unless stimulated with IL1A. Using microRNA (miRNA)-specific bioarrays, Greco and Rameshwar (2007) found that the miRNAs MIRN130A (610175), MIRN206 (611599), and MIRN302A were downregulated by IL1A in MSC-derived neuronal cells. They identified putative binding sites for these miRNAs within the 3-prime UTR of TAC1, and reporter gene assays confirmed the MIRN130A and MIRN206 sites. Specific inhibition of MIRN130A and MIRN206 in MSC-derived neuronal cells resulted in substance P synthesis and release. Greco and Rameshwar (2007) concluded that IL1A alleviates translational repression of TAC1 mRNA through negative effects on miRNAs.
Ben-Sasson et al. (2009) reported that Il1-alpha and Il1-beta, but not other proinflammatory cytokines, markedly induced robust and durable primary and secondary Cd4 (186940) responses in mice, with an increase in cells producing Il17 (603149) and Il4 (147780), as well as serum IgG1 and IgE.
Burzynski et al. (2019) identified a (K)PRS motif for thrombin (F2; 176930) cleavage adjacent to the calpain cleavage site in IL1A in diverse mammalian species. Thrombin cleaved pro-IL1A at the conserved site, resulting in an 18-kD fragment (p18). Macrophages, keratinocytes, and platelets released and/or presented pro-IL1A on their surface to be cleaved and activated by thrombin. ELISA showed that thrombin-activated IL1A was generated during generalized infection in human, as p18 was detected in sera from individuals with sepsis-associated adult respiratory distress syndrome, but not in control individuals.
Association of IL1A Polymorphisms with Periodontitis
Kornman et al. (1997) suggested that genetic polymorphisms of the IL1A and IL1B genes may be associated with severity of periodontitis in adult nonsmokers. The IL1B polymorphism was referred to as IL1B+3953 and the IL1A polymorphism was referred to as IL1A-889. Nonsmokers aged 40 to 60 carrying the '2' allele (in either homozygous or heterozygous state) at both loci were observed to have nearly 19 times the risk of developing severe periodontitis compared to subjects homozygous for the '1' allele at either or both of these loci.
Because of the implication of interleukin-1 in adult periodontitis, Diehl et al. (1999) undertook an evaluation of the role of these IL1A and IL1B polymorphisms in early-onset periodontitis (EOP; see 170650) in 28 African American families and 7 Caucasian-American families with 2 or more affected members. The 2 major EOP subtypes, localized juvenile periodontitis and generalized early-onset periodontitis, encompassing rapidly progressive periodontitis and generalized juvenile periodontitis, were analyzed separately and together. They obtained highly significant evidence of linkage disequilibrium for both groups of generalized EOP subjects. A similar trend was noted for the localized form. The IL1 alleles associated with high risk of EOP had been suggested previously to be correlated with low risk for severe adult periodontitis. Linkage disequilibrium with generalized EOP was equally strong for smoking and nonsmoking subjects. IL1A and IL1B polymorphisms were in strong linkage disequilibrium with each other in Caucasians but not in African Americans. Haplotype analyses evaluating both polymorphisms simultaneously indicated that the IL1B variant is likely to be more important for EOP risk. Sib pair linkage analyses, by contrast, provided only marginal support for a gene of very major effect on EOP risk attributable to these IL1 polymorphisms. Diehl et al. (1999) interpreted their results as indicating that EOP is a complex, oligogenic disorder, with interleukin-1 genetic variation contributing an important but not exclusive influence on disease risk.
Association of IL1A Polymorphisms with Alzheimer Disease
Rogers (2000) reported that inflammation may contribute to the pathophysiology of Alzheimer disease (AD; 104300). Potentially neurotoxic mediators of inflammation such as interleukin-1 are expressed at abnormally high levels by glial cells in AD and may lead to neuronal injury. Du et al. (2000), Grimaldi et al. (2000), and Nicoll et al. (2000) found that polymorphisms of interleukin-1 increased the risk for AD. Specifically, the promoter polymorphism at position -889 showed an association of increased risk for AD with the '2' allele. Murphy et al. (2001) found that in a sample of 114 patients followed for an average of 3.8 years, individuals homozygous for the '1' allele declined significantly more rapidly on the Mini-Mental State Examination than did others. There was no difference in rate of decline between patients with and without the APOE4 allele. The results supported the hypothesis that inflammation is important to the onset and/or clinical course of AD.
McGeer and McGeer (2001) stated that there is evidence that the risk of Alzheimer disease is substantially influenced by a total of 10 polymorphisms in the inflammatory agents IL1A, IL1B, interleukin-6 (IL6; 147620), tumor necrosis factor-alpha (TNFA; 191160), alpha-2-macroglobulin (A2M; 103950), and alpha-1-antichymotrypsin (AACT; 107280). The overall chances of an individual developing AD might be profoundly affected by a 'susceptibility profile' reflecting the combined influence of inheriting multiple high-risk alleles. Since some of the polymorphisms in question have already been linked to peripheral inflammatory disorders, such as juvenile rheumatoid arthritis, myasthenia gravis, and periodontitis, associations between AD and several chronic degenerative diseases may eventually be demonstrated.
In a study of 148 patients with AD, Kolsch et al. (2001) found that carriers of the TT genotype polymorphism at position -889 had a 10-year earlier age of onset of AD than carriers of the CT or CC alleles. The T polymorphism was not found to influence the risk for AD. The authors concluded that the TT genotype is a disease modifier, not a risk factor, for AD.
Ki et al. (2001) analyzed the IL1A -889 C/T genotype of 126 Korean patients with AD and found no significant difference in allele frequencies between patients and controls. Interestingly, there were no T/T homozygotes in the entire study population.
Among 395 patients with AD, Green et al. (2002) found no association between the IL1A -889 and IL1B -511 polymorphisms and increased risk of AD. Among 92 Finnish patients with AD, Mattila et al. (2002) found no association with the IL1A -889 or IL1B -511 polymorphisms.
Association of IL1A Polymorphisms with Osteomyelitis
In a study of 52 patients with osteomyelitis and 109 healthy controls, Asensi et al. (2003) found that the IL1A -889 TT genotype was significantly more frequent among patients than controls (p = 0.0081; OR 3.7) and that patients homozygous for the T allele were significantly younger than the other patients (p = 0.001). The IL1B +3953 TT genotype was also more frequent in patients with osteomyelitis (p = 0.014), but was in linkage disequilibrium with the IL1A T allele (p less than 0.001). Asensi et al. (2003) noted that IL1A serum levels were not significantly higher in patients with the IL1A -889 TT genotype than in those without it.
Association of IL1A Polymorphisms with End-Stage Renal Disease
End-stage renal disease (ESRD) with underlying glomerulosclerosis and fibrosis is a major cause of morbidity and mortality among individuals with diabetes, hypertension, and glomerulonephritis. Bensen et al. (2003) quoted data from the US Renal Data System indicating that the incidence of ESRD increased approximately 50% among all ethnic groups in the United States from 1990 to 2000. While monogenic forms of renal disease exist, ESRD in the general population has a heterogeneous etiology that probably combines both genetic and environmental factors. African Americans are at 4.5-fold higher risk than Caucasians to develop ESRD. Polymorphisms in the IL1 gene cluster on chromosome 2, especially in IL1RN, have been reported to be associated with diabetic nephropathy. Bensen et al. (2003) constructed a dense gene-based single-nucleotide polymorphism (SNP) map across a 360-kb region containing the IL1A, IL1B, and IL1RN gene cluster, focusing on IL1RN. A total of 95 polymorphisms were confirmed or identified primarily by direct sequencing. Single markers and haplotypes in IL1 cluster genes were evaluated for association with ESRD. The strongest associations were found with 2 IL1A variants, a SNP in intron 5 (p = 0.0015) and a 4-bp insertion/deletion within the 3-prime untranslated region, among African Americans with ESRD unrelated to type II diabetes mellitus (125853).
IL1A Intron 6 Repeat Polymorphism
Bailly et al. (1993) elucidated a polymorphism that consists of a variable number of repeats of a 46-bp sequence within intron 6 of the IL1A gene. Among 72 unrelated persons, they identified 6 different alleles ranging from 5 to 18 repeats; the most frequent allele, present in 62%, contained 9 repeats. They suggested that the polymorphism may be of significance in gene function, since each repeat contains 3 potential binding sites for transcription factors.
IL1 Gene Cluster Haplotypes
Cox et al. (1998) carried out studies with multiallelic markers that grouped the IL1A, IL1B, and IL1RN genes into a biallelic system for use in association studies. They identified a common, 8-locus haplotype of the IL1 gene cluster.
Soller et al. (2007) reported that canine Tnf, Il1a, and Il1b have high coding and protein sequence identity to human and other mammalian homologs. They suggested that dog models of cytokine-mediated human diseases may be highly informative.
Using mice lacking both Il1a and Il1b, Oboki et al. (2010) showed that Il1 played a substantial role in the induction of T cell-mediated type IV hypersensitivity, including contact and delayed-type hypersensitivity reactions, and autoimmune diseases, such as experimental autoimmune encephalomyelitis, a model for multiple sclerosis (MS; 126200).
Burzynski et al. (2019) found that transgenic mice carrying a mutation in the (K)PRS motif of Il1a had no phenotypic differences compared with controls. Thrombin did not cleave surface pro-Il1a on macrophages from transgenic mice. Transgenic mice exhibited delayed platelet recovery after depletion compared with controls. Failure to generate activated Il1a in transgenic mice resulted in reduced immune-cell recruitment to epidermal wound sites, causing delayed excisional wound closure. Thrombin cleavage and activation of Il1a took place after epidermal injury, as inhibition of thrombin reduced cleaved Il1a production from wounds in control mice.
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