• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Jun 15, 1991; 88(12): 5232–5236.

Interleukin 1 receptor antagonist is a member of the interleukin 1 gene family: evolution of a cytokine control mechanism.


Interleukin 1 receptor antagonist (IL-1ra) is a protein that binds to the IL-1 receptor and blocks the binding of both IL-1 alpha and -beta without inducing a signal of its own. Human IL-1ra has some sequence identity to human IL-1 beta, but the evolutionary relationship between these proteins has been unclear. We show that the genes for human, mouse, and rat IL-1ra are similar to the genes for IL-1 alpha and IL-1 beta in intron-exon organization, indicating that gene duplication events were important in the creation of this gene family. Furthermore, an analysis of sequence comparisons and mutation rates for IL-1 alpha, IL-1 beta, and IL-1ra suggests that the duplication giving rise to the IL-1ra gene was an early event in the evolution of the gene family. Comparisons between the mature sequences for IL-1ra, IL-1 alpha, and IL-1 beta suggest that IL-1ra has a beta-stranded structure like to IL-1 alpha and IL-1 beta, consistent with the three proteins being related. The N-terminal sequences of IL-1ra appear to be derived from a region of the genome different than those of IL-1 alpha and IL-1 beta, thus explaining their different modes of biosynthesis and suggesting an explanation for their different biological activities.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Dinarello CA. Biology of interleukin 1. FASEB J. 1988 Feb;2(2):108–115. [PubMed]
  • Maliszewski CR, Baker PE, Schoenborn MA, Davis BS, Cosman D, Gillis S, Cerretti DP. Cloning, sequence and expression of bovine interleukin 1 alpha and interleukin 1 beta complementary DNAs. Mol Immunol. 1988 May;25(5):429–437. [PubMed]
  • Dower SK, Kronheim SR, Hopp TP, Cantrell M, Deeley M, Gillis S, Henney CS, Urdal DL. The cell surface receptors for interleukin-1 alpha and interleukin-1 beta are identical. Nature. 1986 Nov 20;324(6094):266–268. [PubMed]
  • Kilian PL, Kaffka KL, Stern AS, Woehle D, Benjamin WR, Dechiara TM, Gubler U, Farrar JJ, Mizel SB, Lomedico PT. Interleukin 1 alpha and interleukin 1 beta bind to the same receptor on T cells. J Immunol. 1986 Jun 15;136(12):4509–4514. [PubMed]
  • Matsushima K, Akahoshi T, Yamada M, Furutani Y, Oppenheim JJ. Properties of a specific interleukin 1 (IL 1) receptor on human Epstein Barr virus-transformed B lymphocytes: identity of the receptor for IL 1-alpha and IL 1-beta. J Immunol. 1986 Jun 15;136(12):4496–4502. [PubMed]
  • Larrick JW. Native interleukin 1 inhibitors. Immunol Today. 1989 Feb;10(2):61–66. [PubMed]
  • Arend WP, Dayer JM. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 1990 Mar;33(3):305–315. [PubMed]
  • Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. [PubMed]
  • Eisenberg SP, Evans RJ, Arend WP, Verderber E, Brewer MT, Hannum CH, Thompson RC. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990 Jan 25;343(6256):341–346. [PubMed]
  • Stetler G, Brewer MT, Thompson RC. Isolation and sequence of a human gene encoding a potent inhibitor of leukocyte proteases. Nucleic Acids Res. 1986 Oct 24;14(20):7883–7896. [PMC free article] [PubMed]
  • Wyman AR, Wertman KF. Host strains that alleviate underrepresentation of specific sequences: overview. Methods Enzymol. 1987;152:173–180. [PubMed]
  • Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. [PubMed]
  • Wood WI. Gene cloning based on long oligonucleotide probes. Methods Enzymol. 1987;152:443–447. [PubMed]
  • Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. [PubMed]
  • Herrmann BG, Frischauf AM. Isolation of genomic DNA. Methods Enzymol. 1987;152:180–183. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PMC free article] [PubMed]
  • Maxam AM, Gilbert W. A new method for sequencing DNA. Proc Natl Acad Sci U S A. 1977 Feb;74(2):560–564. [PMC free article] [PubMed]
  • Breathnach R, Chambon P. Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem. 1981;50:349–383. [PubMed]
  • Li WH, Tanimura M, Sharp PM. An evaluation of the molecular clock hypothesis using mammalian DNA sequences. J Mol Evol. 1987;25(4):330–342. [PubMed]
  • Graves BJ, Hatada MH, Hendrickson WA, Miller JK, Madison VS, Satow Y. Structure of interleukin 1 alpha at 2.7-A resolution. Biochemistry. 1990 Mar 20;29(11):2679–2684. [PubMed]
  • Auron PE, Webb AC, Rosenwasser LJ, Mucci SF, Rich A, Wolff SM, Dinarello CA. Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7907–7911. [PMC free article] [PubMed]
  • March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, Gillis S, Henney CS, Kronheim SR, Grabstein K, et al. Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature. 1985 Jun 20;315(6021):641–647. [PubMed]
  • Lomedico PT, Gubler U, Hellmann CP, Dukovich M, Giri JG, Pan YC, Collier K, Semionow R, Chua AO, Mizel SB. Cloning and expression of murine interleukin-1 cDNA in Escherichia coli. Nature. 312(5993):458–462. [PubMed]
  • Gray PW, Glaister D, Chen E, Goeddel DV, Pennica D. Two interleukin 1 genes in the mouse: cloning and expression of the cDNA for murine interleukin 1 beta. J Immunol. 1986 Dec 1;137(11):3644–3648. [PubMed]
  • Furutani Y, Notake M, Yamayoshi M, Yamagishi J, Nomura H, Ohue M, Furuta R, Fukui T, Yamada M, Nakamura S. Cloning and characterization of the cDNAs for human and rabbit interleukin-1 precursor. Nucleic Acids Res. 1985 Aug 26;13(16):5869–5882. [PMC free article] [PubMed]
  • Mori S, Goto F, Goto K, Ohkawara S, Maeda S, Shimada K, Yoshinaga M. Cloning and sequence analysis of a cDNA for lymphocyte proliferation potentiating factor of rabbit polymorphonuclear leukocytes: identification rabbit interleukin 1 beta. Biochem Biophys Res Commun. 1988 Feb 15;150(3):1237–1243. [PubMed]
  • Finzel BC, Clancy LL, Holland DR, Muchmore SW, Watenpaugh KD, Einspahr HM. Crystal structure of recombinant human interleukin-1 beta at 2.0 A resolution. J Mol Biol. 1989 Oct 20;209(4):779–791. [PubMed]
  • Furutani Y, Notake M, Fukui T, Ohue M, Nomura H, Yamada M, Nakamura S. Complete nucleotide sequence of the gene for human interleukin 1 alpha. Nucleic Acids Res. 1986 Apr 25;14(8):3167–3179. [PMC free article] [PubMed]
  • Clark BD, Collins KL, Gandy MS, Webb AC, Auron PE. Genomic sequence for human prointerleukin 1 beta: possible evolution from a reverse transcribed prointerleukin 1 alpha gene. Nucleic Acids Res. 1986 Oct 24;14(20):7897–7914. [PMC free article] [PubMed]
  • Telford JL, Macchia G, Massone A, Carinci V, Palla E, Melli M. The murine interleukin 1 beta gene: structure and evolution. Nucleic Acids Res. 1986 Dec 22;14(24):9955–9963. [PMC free article] [PubMed]
  • Bensi G, Raugei G, Palla E, Carinci V, Tornese Buonamassa D, Melli M. Human interleukin-1 beta gene. Gene. 1987;52(1):95–101. [PubMed]
  • Cunningham BC, Henner DJ, Wells JA. Engineering human prolactin to bind to the human growth hormone receptor. Science. 1990 Mar 23;247(4949 Pt 1):1461–1465. [PubMed]
  • Mollison KW, Mandecki W, Zuiderweg ER, Fayer L, Fey TA, Krause RA, Conway RG, Miller L, Edalji RP, Shallcross MA, et al. Identification of receptor-binding residues in the inflammatory complement protein C5a by site-directed mutagenesis. Proc Natl Acad Sci U S A. 1989 Jan;86(1):292–296. [PMC free article] [PubMed]
  • Hazuda DJ, Strickler J, Kueppers F, Simon PL, Young PR. Processing of precursor interleukin 1 beta and inflammatory disease. J Biol Chem. 1990 Apr 15;265(11):6318–6322. [PubMed]
  • Black RA, Kronheim SR, Sleath PR. Activation of interleukin-1 beta by a co-induced protease. FEBS Lett. 1989 Apr 24;247(2):386–390. [PubMed]
  • Kostura MJ, Tocci MJ, Limjuco G, Chin J, Cameron P, Hillman AG, Chartrain NA, Schmidt JA. Identification of a monocyte specific pre-interleukin 1 beta convertase activity. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5227–5231. [PMC free article] [PubMed]
  • Kobayashi Y, Yamamoto K, Saido T, Kawasaki H, Oppenheim JJ, Matsushima K. Identification of calcium-activated neutral protease as a processing enzyme of human interleukin 1 alpha. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5548–5552. [PMC free article] [PubMed]
  • Burgess WH, Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem. 1989;58:575–606. [PubMed]
  • Gehrke L, Jobling SA, Paik LS, McDonald B, Rosenwasser LJ, Auron PE. A point mutation uncouples human interleukin-1 beta biological activity and receptor binding. J Biol Chem. 1990 Apr 15;265(11):5922–5925. [PubMed]
  • Young PR, Sylvester D. Cloning of rabbit interleukin-1 beta: differential evolution of IL-1 alpha and IL-1 beta proteins. Protein Eng. 1989 May;2(7):545–551. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene links
  • MedGen
    Related information in MedGen
  • Nucleotide
    Published Nucleotide sequences
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • Protein
    Published protein sequences
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...