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Gene Review

IL1A  -  interleukin 1, alpha

Homo sapiens

Synonyms: Hematopoietin-1, IL-1 alpha, IL-1A, IL1, IL1-ALPHA, ...
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Disease relevance of IL1A

  • Identification of an IL1A gene segment that determines aberrant constitutive expression of interleukin-1 alpha in systemic sclerosis [1].
  • Eleven SNPs show some evidence of association with ESRD, with the strongest associations in two IL1A variants, one SNP, rs1516792-3, in intron 5 (p=0.0015) and a 4-bp insertion/deletion within the 3'UTR, rs16347-2 (p=0.0024), among African Americans with non-T2DM-associated ESRD [2].
  • CONCLUSION: We investigated interleukin polymorphisms in ovarian cancer but did not find any association between common polymorphisms of IL1A, IL1B, and IL1RN and the occurrence of ovarian cancer [3].
  • Analysis of IL6 and IL1A gene polymorphisms in UK and Dutch patients with sarcoidosis [4].
  • Association analysis of IL1A and IL1B variants in alopecia areata [5].

Psychiatry related information on IL1A


High impact information on IL1A

  • Studies in the early to mid 1980s demonstrated that monocyte-derived or recombinant interleukin-1 (IL-1) causes secretion of hormones of the hypothalamic-pituitary-adrenal (HPA) axis, establishing that immunoregulators, known as cytokines, play a pivotal role in this bidirectional communication between the immune and neuroendocrine systems [11].
  • We found and replicated association between asthma and the D2S308 microsatellite, 800 kb distal to the IL1 cluster on 2q14 [12].
  • Activation of the transcription factor NF-kappaB by tumor necrosis factor (TNF) and interleukin-1 (IL-1) requires the NF-kappaB-inducing kinase (NIK) [13].
  • An IL-1-stimulated protein kinase cascade resulting in phosphorylation of the small heat shock protein hsp27 has been identified in KB cells [14].
  • Twenty weeks after the end of supplementation, the production of IL-1 beta, IL-1 alpha, and tumor necrosis factor had returned to the presupplement level [15].

Chemical compound and disease context of IL1A

  • However, delaying the initial IL-1ra treatment 3 hours after the induction of colitis (total 6 doses) was effective in reducing inflammatory index (by 60%), MPO activity (by 79%), PGE2 (by 62%), and LTB4 (by 72%) whereas colonic IL-1 alpha levels were unchanged compared with vehicle-treated animals [16].
  • Incubation with different stimuli (lipopolysaccharide [LPS], phytohemagglutinin [PHA], Staphylococcus epidermidis, or IL-1 alpha) resulted in production of IL-6 [17].
  • The levels of IL-1 and TNF produced in vitro peaked at 24 hours of culture and correlated with stage and the presence (or absence) of extensive osteolytic bone disease [18].
  • One hour after the start of the 30-min IL-1 infusion, which caused mild cardiovascular toxicity, plasma levels of IL-6 reached a peak of 25 +/- 9 ng/L (mean +/- SEM), IL-8 reached a peak of 311 +/- 100 ng/L at 2 h, and nitrite/nitrate peaked after 10 h to 89 +/- 27 mumol/L [19].
  • These results suggest that: (1) IL-1 and TNF stimulate bone resorption in part by increasing osteoclast formation and (2) an extremely low concentration of these factors can synergistically increase osteoclast formation in the absence of other factors, such as 1,25-(OH)2D3 [20].

Biological context of IL1A

  • CONCLUSION: These findings suggest that a DNA binding protein containing the Ets domain is constitutively expressed only in fibroblasts from the affected skin of SSc patients and regulates the transcription of the IL1A gene, which contributes to the fibrogenic phenotype of fibroblasts in SSc [1].
  • CONCLUSION: Our observations suggest that the CTG haplotype of the IL1A gene may be an important marker for the susceptibility to, and the severity of, SSc [21].
  • The DNA protein binding activity for the cis-element of the IL1A gene was determined by electrophoretic mobility shift assay (EMSA) [1].
  • RESULTS: We confirmed the presence of 2 SNPs at positions -889 (C/T) and +4845 (G/T) of the IL1A gene, as previously reported [21].
  • A reporter construct (pLuc.-1437) was prepared that contained a 1.5-kb genomic fragment extending from -1437 to +39 relative to the transcription start site of the IL1A gene inserted upstream of the luciferase gene [1].

Anatomical context of IL1A


Associations of IL1A with chemical compounds


Physical interactions of IL1A

  • IL-1ra competitively inhibits binding of both IL-1 alpha and IL-1 beta to cell surface receptors without inducing any discernible intracellular responses [29].
  • Cell-associated IL-1, particularly IL-1 alpha and membrane-bound TNF alpha, can also play a crucial role in the process of cell-cell interaction [30].
  • By contrast, the initial translation product of IL-1 alpha mRNA can bind to the IL-1 receptor without further proteolytic processing [31].
  • However, after a 2-day LDL incubation, NF-kappa B binding could be induced by over 63% with a very low dose of IL-1 alpha [32].
  • Internalization at 37 degrees C demonstrated that only 19% of IL-1 beta was internalized and that binding with IL-1 alpha was entirely cell surface [33].

Regulatory relationships of IL1A


Other interactions of IL1A

  • Two distinct but distantly related complementary DNAs encoding proteins sharing human interleukin-1 (IL-1) activity (termed IL-1 alpha and IL-1 beta), were isolated from a macrophage cDNA library [39].
  • Second, sCD23 triggers the release of other inflammatory mediators such as IL-1 alpha, IL-1 beta, and IL-6 [40].
  • The ratio of IL-1ra to IL-1 alpha proteins was significantly increased in involved psoriatic skin compared with normal skin [41].
  • IL-1 alpha induction of TNF receptors reaches a peak after 6 hours and gradually returns to baseline level by 24 hours [35].
  • Colony formation of both lines was uninfluenced by IL1 alpha or IL-3 [42].

Analytical, diagnostic and therapeutic context of IL1A


  1. Identification of an IL1A gene segment that determines aberrant constitutive expression of interleukin-1 alpha in systemic sclerosis. Kawaguchi, Y., Hara, M., Kamatani, N., Wright, T.M. Arthritis Rheum. (2003) [Pubmed]
  2. Nucleotide variation, haplotype structure, and association with end-stage renal disease of the human interleukin-1 gene cluster. Bensen, J.T., Langefeld, C.D., Hawkins, G.A., Green, L.E., Mychaleckyj, J.C., Brewer, C.S., Kiger, D.S., Binford, S.M., Colicigno, C.J., Allred, D.C., Freedman, B.I., Bowden, D.W. Genomics (2003) [Pubmed]
  3. Polymorphisms of the interleukin-1 gene cluster and ovarian cancer. Hefler, L.A., Ludwig, E., Lebrecht, A., Zeillinger, R., Tong-Cacsire, D., Koelbl, H., Leodolter, S., Tempfer, C.B. J. Soc. Gynecol. Investig. (2002) [Pubmed]
  4. Analysis of IL6 and IL1A gene polymorphisms in UK and Dutch patients with sarcoidosis. Grutters, J.C., Sato, H., Pantelidis, P., Ruven, H.J., McGrath, D.S., Wells, A.U., van den Bosch, J.M., Welsh, K.I., du Bois, R.M. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG / World Association of Sarcoidosis and Other Granulomatous Disorders. (2003) [Pubmed]
  5. Association analysis of IL1A and IL1B variants in alopecia areata. Tazi-Ahnini, R., McDonagh, A.J., Cox, A., Messenger, A.G., Britton, J.E., Ward, S.J., Båvik, C.O., Duff, G.W., Cork, M.J. Heredity (2001) [Pubmed]
  6. Interleukin 1 alpha gene polymorphism as a susceptibility factor in Alzheimer's disease and its influence on the extent of histopathological hallmark lesions of Alzheimer's disease. Pirskanen, M., Hiltunen, M., Mannermaa, A., Iivonen, S., Helisalmi, S., Lehtovirta, M., Koivisto, A.M., Laakso, M., Soininen, H., Alafuzoff, I. Dementia and geriatric cognitive disorders. (2002) [Pubmed]
  7. Association of IL-1 RN*2 allele and methionine synthase 2756 AA genotype with dementia severity of sporadic Alzheimer's disease. Bosco, P., Guéant-Rodríguez, R.M., Anello, G., Romano, A., Namour, B., Spada, R.S., Caraci, F., Tringali, G., Ferri, R., Guéant, J.L. J. Neurol. Neurosurg. Psychiatr. (2004) [Pubmed]
  8. The biology of interleukin 1 and comparison to tumor necrosis factor. Dinarello, C.A. Immunol. Lett. (1987) [Pubmed]
  9. Interleukin 1 induces interleukin 1. I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. Dinarello, C.A., Ikejima, T., Warner, S.J., Orencole, S.F., Lonnemann, G., Cannon, J.G., Libby, P. J. Immunol. (1987) [Pubmed]
  10. Correlation between serum levels of interleukin-4 and alexithymia scores in healthy female subjects: preliminary findings. Corcos, M., Guilbaud, O., Paterniti, S., Curt, F., Hjalmarsson, L., Moussa, M., Chambry, J., Loas, G., Chaouat, G., Jeammet, P. Psychoneuroendocrinology (2004) [Pubmed]
  11. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Turnbull, A.V., Rivier, C.L. Physiol. Rev. (1999) [Pubmed]
  12. Positional cloning of a novel gene influencing asthma from chromosome 2q14. Allen, M., Heinzmann, A., Noguchi, E., Abecasis, G., Broxholme, J., Ponting, C.P., Bhattacharyya, S., Tinsley, J., Zhang, Y., Holt, R., Jones, E.Y., Lench, N., Carey, A., Jones, H., Dickens, N.J., Dimon, C., Nicholls, R., Baker, C., Xue, L., Townsend, E., Kabesch, M., Weiland, S.K., Carr, D., von Mutius, E., Adcock, I.M., Barnes, P.J., Lathrop, G.M., Edwards, M., Moffatt, M.F., Cookson, W.O. Nat. Genet. (2003) [Pubmed]
  13. Identification and characterization of an IkappaB kinase. Régnier, C.H., Song, H.Y., Gao, X., Goeddel, D.V., Cao, Z., Rothe, M. Cell (1997) [Pubmed]
  14. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Freshney, N.W., Rawlinson, L., Guesdon, F., Jones, E., Cowley, S., Hsuan, J., Saklatvala, J. Cell (1994) [Pubmed]
  15. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. Endres, S., Ghorbani, R., Kelley, V.E., Georgilis, K., Lonnemann, G., van der Meer, J.W., Cannon, J.G., Rogers, T.S., Klempner, M.S., Weber, P.C. N. Engl. J. Med. (1989) [Pubmed]
  16. Recombinant interleukin-1 receptor antagonist blocks the proinflammatory activity of endogenous interleukin-1 in rabbit immune colitis. Cominelli, F., Nast, C.C., Duchini, A., Lee, M. Gastroenterology (1992) [Pubmed]
  17. Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Schindler, R., Mancilla, J., Endres, S., Ghorbani, R., Clark, S.C., Dinarello, C.A. Blood (1990) [Pubmed]
  18. Production of cytokines by bone marrow cells obtained from patients with multiple myeloma. Lichtenstein, A., Berenson, J., Norman, D., Chang, M.P., Carlile, A. Blood (1989) [Pubmed]
  19. IL-1 beta does not cause neutrophil degranulation but does lead to IL-6, IL-8, and nitrite/nitrate release when used in patients with cancer. Ogilvie, A.C., Hack, C.E., Wagstaff, J., van Mierlo, G.J., Erenberg, A.J., Thomsen, L.L., Hoekman, K., Rankin, E.M. J. Immunol. (1996) [Pubmed]
  20. Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclastlike cells in vitro. Pfeilschifter, J., Chenu, C., Bird, A., Mundy, G.R., Roodman, G.D. J. Bone Miner. Res. (1989) [Pubmed]
  21. Association of IL1A gene polymorphisms with susceptibility to and severity of systemic sclerosis in the Japanese population. Kawaguchi, Y., Tochimoto, A., Ichikawa, N., Harigai, M., Hara, M., Kotake, S., Kitamura, Y., Kamatani, N. Arthritis Rheum. (2003) [Pubmed]
  22. Adhesion of human basophils, eosinophils, and neutrophils to interleukin 1-activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules. Bochner, B.S., Luscinskas, F.W., Gimbrone, M.A., Newman, W., Sterbinsky, S.A., Derse-Anthony, C.P., Klunk, D., Schleimer, R.P. J. Exp. Med. (1991) [Pubmed]
  23. Regulation of cytokine production in the human thymus: epidermal growth factor and transforming growth factor alpha regulate mRNA levels of interleukin 1 alpha (IL-1 alpha), IL-1 beta, and IL-6 in human thymic epithelial cells at a post-transcriptional level. Le, P.T., Lazorick, S., Whichard, L.P., Haynes, B.F., Singer, K.H. J. Exp. Med. (1991) [Pubmed]
  24. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. McIntyre, K.W., Stepan, G.J., Kolinsky, K.D., Benjamin, W.R., Plocinski, J.M., Kaffka, K.L., Campen, C.A., Chizzonite, R.A., Kilian, P.L. J. Exp. Med. (1991) [Pubmed]
  25. Human interleukin 1 induces interleukin 1 gene expression in human vascular smooth muscle cells. Warner, S.J., Auger, K.R., Libby, P. J. Exp. Med. (1987) [Pubmed]
  26. Alleles of the gene encoding IL-1alpha may predict control of plasma viraemia in HIV-1 patients on highly active antiretroviral therapy. Price, P., James, I., Fernandez, S., French, M.A. AIDS (2004) [Pubmed]
  27. Identification of a high-affinity receptor for native human interleukin 1 beta and interleukin 1 alpha on normal human lung fibroblasts. Chin, J., Cameron, P.M., Rupp, E., Schmidt, J.A. J. Exp. Med. (1987) [Pubmed]
  28. Tissue interleukin 1 and interleukin-1 receptor antagonist expression in enterocolitis in resistant and susceptible rats. McCall, R.D., Haskill, S., Zimmermann, E.M., Lund, P.K., Thompson, R.C., Sartor, R.B. Gastroenterology (1994) [Pubmed]
  29. Interleukin-1 receptor antagonist. Arend, W.P. Adv. Immunol. (1993) [Pubmed]
  30. Adhesion molecules and cytokine production. Dayer, J.M., Isler, P., Nicod, L.P. Am. Rev. Respir. Dis. (1993) [Pubmed]
  31. The interleukin-1 receptor binds the human interleukin-1 alpha precursor but not the interleukin-1 beta precursor. Mosley, B., Urdal, D.L., Prickett, K.S., Larsen, A., Cosman, D., Conlon, P.J., Gillis, S., Dower, S.K. J. Biol. Chem. (1987) [Pubmed]
  32. Low-density lipoprotein augments interleukin-1-induced vascular adhesion molecule expression in human endothelial cells. Zhu, Y., Liao, H.L., Lin, J.H., Verna, L., Stemerman, M.B. Atherosclerosis (1999) [Pubmed]
  33. Heterogeneity in interleukin (IL)-1 receptors expressed on human B cell lines. Differences in the molecular properties of IL-1 alpha and IL-1 beta binding sites. Benjamin, D., Wormsley, S., Dower, S.K. J. Biol. Chem. (1990) [Pubmed]
  34. Expression of interleukin 1-inducible genes and production of interleukin 1 by aging human fibroblasts. Kumar, S., Millis, A.J., Baglioni, C. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  35. Interleukin-1 alpha upregulates tumor necrosis factor receptors expressed by a human bone marrow stromal cell strain: implications for cytokine redundancy and synergy. Caldwell, J., Emerson, S.G. Blood (1995) [Pubmed]
  36. Interleukin-1 accelerates autocrine growth of myeloma cells through interleukin-6 in human myeloma. Kawano, M., Tanaka, H., Ishikawa, H., Nobuyoshi, M., Iwato, K., Asaoku, H., Tanabe, O., Kuramoto, A. Blood (1989) [Pubmed]
  37. IL-1 induces IL-1. IV. IFN-gamma suppresses IL-1 but not lipopolysaccharide-induced transcription of IL-1. Schindler, R., Ghezzi, P., Dinarello, C.A. J. Immunol. (1990) [Pubmed]
  38. IL-4 expression in human T cells is selectively inhibited by IL-1 alpha and IL-1 beta. Sandborg, C.I., Imfeld, K.L., Zaldivar, F., Wang, Z., Buckingham, B.A., Berman, M.A. J. Immunol. (1995) [Pubmed]
  39. Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. March, C.J., Mosley, B., Larsen, A., Cerretti, D.P., Braedt, G., Price, V., Gillis, S., Henney, C.S., Kronheim, S.R., Grabstein, K. Nature (1985) [Pubmed]
  40. Regulation of cytokine production by soluble CD23: costimulation of interferon gamma secretion and triggering of tumor necrosis factor alpha release. Armant, M., Ishihara, H., Rubio, M., Delespesse, G., Sarfati, M. J. Exp. Med. (1994) [Pubmed]
  41. Interleukin-1 receptor antagonist in normal and psoriatic epidermis. Hammerberg, C., Arend, W.P., Fisher, G.J., Chan, L.S., Berger, A.E., Haskill, J.S., Voorhees, J.J., Cooper, K.D. J. Clin. Invest. (1992) [Pubmed]
  42. Production of growth factors by malignant lymphoma cell lines. Tweeddale, M., Jamal, N., Nguyen, A., Wang, X.H., Minden, M.D., Messner, H.A. Blood (1989) [Pubmed]
  43. The IL1A genotype associates with atopy in nonasthmatic adults. Karjalainen, J., Hulkkonen, J., Pessi, T., Huhtala, H., Nieminen, M.M., Aromaa, A., Klaukka, T., Hurme, M. J. Allergy Clin. Immunol. (2002) [Pubmed]
  44. Functional correlates of the interleukin-1 receptor antagonist gene polymorphism in the colonic mucosa in ulcerative colitis. Carter, M.J., Jones, S., Camp, N.J., Cox, A., Mee, J., Warren, B., Duff, G.W., Lobo, A.J., di Giovine, F.S. Genes Immun. (2004) [Pubmed]
  45. Interleukin 1 gene expression in adult T cell leukemia. Wano, Y., Hattori, T., Matsuoka, M., Takatsuki, K., Chua, A.O., Gubler, U., Greene, W.C. J. Clin. Invest. (1987) [Pubmed]
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