Interleukin 1 receptor antagonist
The interleukin-1 receptor antagonist (IL-1RA) is a protein that in humans is encoded by the IL1RN gene.[1][2]
IL-1RA was initially called the IL-1 inhibitor and was discovered separately in 1984 by two independent laboratories.[3] IL-1RA, is an agent that binds non-productively to the cell surface interleukin-1 receptor (IL-1R). IL-1R is the same receptor that binds interleukin 1 (IL-1). Hence IL-1RA prevents IL-1 from sending a signal to that cell.
Function
IL-1RA is a member of the interleukin 1 cytokine family. IL1Ra is secreted by various types of cells including immune cells, epithelial cells, and adipocytes, and is a natural inhibitor of the pro-inflammatory effect of IL1β. [4]. This protein inhibits the activities of interleukin 1, alpha (IL1A) and interleukin 1, beta (IL1B), and modulates a variety of interleukin 1 related immune and inflammatory responses. This gene and five other closely related cytokine genes form a gene cluster spanning approximately 400 kb on chromosome 2. Four alternatively spliced transcript variants encoding distinct isoforms have been reported.[5]
Clinical significance
A polymorphism of this gene is reported to be associated with increased risk of osteoporotic fractures[6] and gastric cancer.[7]
Mutations in the IL1RN gene results in a rare disease called deficiency of the interleukin-1–receptor antagonist (DIRA).[8] Variants of the IL1RN gene is also associated with risk of schizophrenia.[9][10] Elevated levels of IL1RN has been found in serum of schizophrenia patients.[11]
An interleukin 1 receptor antagonist is used in the treatment of rheumatoid arthritis, an autoimmune disease in which IL-1 plays a key role. It is commercially produced as anakinra, which is a human recombinant form of IL-1RA. In terms of protein similarities, IL-1β is more closely related to IL-1RA than it is to IL- 1α. The amino acids that are identical between mature human IL-1α and mature IL-1β is 22% while it is 26% when comparing IL-1β to IL-1RA and only 18% when comparing IL-1α to IL-1RA.[3]
References
- ^ Steinkasserer A, Spurr NK, Cox S, Jeggo P, Sim RB (July 1992). "The human IL-1 receptor antagonist gene (IL1RN) maps to chromosome 2q14-q21, in the region of the IL-1 alpha and IL-1 beta loci". Genomics 13 (3): 654–7. doi:10.1016/0888-7543(92)90137-H. PMID 1386337.
- ^ Patterson D, Jones C, Hart I, Bleskan J, Berger R, Geyer D, Eisenberg SP, Smith MF, Arend WP (January 1993). "The human interleukin-1 receptor antagonist (IL1RN) gene is located in the chromosome 2q14 region". Genomics 15 (1): 173–6. doi:10.1006/geno.1993.1025. PMID 8432529.
- ^ a b Dinarello CA (December 1994). "The interleukin-1 family: 10 years of discovery". FASEB J. 8 (15): 1314–25. PMID 8001745.
- ^ Perrier S, Darakhshan F, Hajduch E. (2006) IL-1 receptor antagonist in metabolic diseases: Dr Jekyll or Mr Hyde? FEBS Lett. 580(27):6289-94> http://www.ncbi.nlm.nih.gov/pubmed/17097645
- ^ "Entrez Gene: IL1RN interleukin 1 receptor antagonist". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3557.
- ^ Langdahl BL, Løkke E, Carstens M, Stenkjaer LL, Eriksen EF (March 2000). "Osteoporotic fractures are associated with an 86-base pair repeat polymorphism in the interleukin-1--receptor antagonist gene but not with polymorphisms in the interleukin-1beta gene". J. Bone Miner. Res. 15 (3): 402–14. doi:10.1359/jbmr.2000.15.3.402. PMID 10750554.
- ^ El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF, Rabkin CS (March 2000). "Interleukin-1 polymorphisms associated with increased risk of gastric cancer". Nature 404 (6776): 398–402. doi:10.1038/35006081. PMID 10746728.
- ^ Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, Laxer R, Tedgård U, Cowen EW, Pham TH, Booty M, Estes JD, Sandler NG, Plass N, Stone DL, Turner ML, Hill S, Butman JA, Schneider R, Babyn P, El-Shanti HI, Pope E, Barron K, Bing X, Laurence A, Lee CC, Chapelle D, Clarke GI, Ohson K, Nicholson M, Gadina M, Yang B, Korman BD, Gregersen PK, van Hagen PM, Hak AE, Huizing M, Rahman P, Douek DC, Remmers EF, Kastner DL, Goldbach-Mansky R (June 2009). "An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist". N. Engl. J. Med. 360 (23): 2426–37. doi:10.1056/NEJMoa0807865. PMC 2876877. PMID 19494218. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2876877.
- ^ Kim SJ, Lee HJ, Koo HG, Kim JW, Song JY, Kim MK, Shin DH, Jin SY, Hong MS, Park HJ, Yoon SH, Park HK, Chung JH (September 2004). "Impact of IL-1 receptor antagonist gene polymorphism on schizophrenia and bipolar disorder". Psychiatr. Genet. 14 (3): 165–7. doi:10.1097/00041444-200409000-00009. PMID 15318032.
- ^ Zanardini R, Bocchio-Chiavetto L, Scassellati C, Bonvicini C, Tura GB, Rossi G, Perez J, Gennarelli M (2003). "Association between IL-1beta -511C/T and IL-1RA (86bp)n repeats polymorphisms and schizophrenia". J Psychiatr Res 37 (6): 457–62. doi:10.1016/S0022-3956(03)00072-4. PMID 14563376.
- ^ Hope S, Melle I, Aukrust P, Steen NE, Birkenaes AB, Lorentzen S, Agartz I, Ueland T, Andreassen OA (November 2009). "Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor". Bipolar Disord 11 (7): 726–34. doi:10.1111/j.1399-5618.2009.00757.x. PMID 19839997.
Further reading
- Arend WP, Malyak M, Guthridge CJ, Gabay C (1998). "Interleukin-1 receptor antagonist: role in biology". Annu. Rev. Immunol. 16: 27–55. doi:10.1146/annurev.immunol.16.1.27. PMID 9597123.
- Adcock IM, Ito K (2000). "Molecular mechanisms of corticosteroid actions". Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS [and] Istituto di clinica tisiologica e malattie apparato respiratorio, Università di Napoli, Secondo ateneo 55 (3): 256–66. PMID 10948677.
- Arend WP (2003). "The balance between IL-1 and IL-1Ra in disease". Cytokine Growth Factor Rev. 13 (4–5): 323–40. doi:10.1016/S1359-6101(02)00020-5. PMID 12220547.
- Sehouli J, Mustea A, Könsgen D, et al. (2003). "Polymorphism of IL-1 receptor antagonist gene: role in cancer". Anticancer Res. 22 (6A): 3421–4. PMID 12530098.
- Kamangar F, Cheng C, Abnet CC, Rabkin CS (2007). "Interleukin-1B polymorphisms and gastric cancer risk--a meta-analysis". Cancer Epidemiol. Biomarkers Prev. 15 (10): 1920–8. doi:10.1158/1055-9965.EPI-06-0267. PMID 17035400.
External links
|
PDB gallery
|
|
|
|
1ilr: CRYSTAL STRUCTURE OF THE INTERLEUKIN-1 RECEPTOR ANTAGONIST
|
|
|
1ira: COMPLEX OF THE INTERLEUKIN-1 RECEPTOR WITH THE INTERLEUKIN-1 RECEPTOR ANTAGONIST (IL1RA)
|
|
|
1irp: SOLUTION STRUCTURE OF HUMAN INTERLEUKIN-1 RECEPTOR ANTAGONIST PROTEIN
|
|
|
|
|
|
|
| By family |
|
|
|
|
|
|
|
|
|
|
Type I
(grouped by
receptor
subunit)
|
|
|
|
|
|
|
|
|
|
|
|
|
IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21, IFNB1, IFNK, IFNW1
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Other
|
|
|
|
By function/
cell |
|
|
|
B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
|
|