Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Jun 15;88(12):5232–5236. doi: 10.1073/pnas.88.12.5232

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

S P Eisenberg 1, M T Brewer 1, E Verderber 1, P Heimdal 1, B J Brandhuber 1, R C Thompson 1
PMCID: PMC51846  PMID: 1828896

Abstract

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

PDF
5232

Images in this article

5235Image
on p.5235
5235Image
on p.5235

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arend W. P., Dayer J. M. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 1990 Mar;33(3):305–315. doi: 10.1002/art.1780330302. [DOI] [PubMed] [Google Scholar]
  2. Auron P. E., Webb A. C., Rosenwasser L. J., Mucci S. F., Rich A., Wolff S. M., Dinarello C. A. Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7907–7911. doi: 10.1073/pnas.81.24.7907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bensi G., Raugei G., Palla E., Carinci V., Tornese Buonamassa D., Melli M. Human interleukin-1 beta gene. Gene. 1987;52(1):95–101. doi: 10.1016/0378-1119(87)90398-2. [DOI] [PubMed] [Google Scholar]
  4. Black R. A., Kronheim S. R., Sleath P. R. Activation of interleukin-1 beta by a co-induced protease. FEBS Lett. 1989 Apr 24;247(2):386–390. doi: 10.1016/0014-5793(89)81376-6. [DOI] [PubMed] [Google Scholar]
  5. Breathnach R., Chambon P. Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem. 1981;50:349–383. doi: 10.1146/annurev.bi.50.070181.002025. [DOI] [PubMed] [Google Scholar]
  6. Burgess W. H., Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem. 1989;58:575–606. doi: 10.1146/annurev.bi.58.070189.003043. [DOI] [PubMed] [Google Scholar]
  7. Clark B. D., Collins K. L., Gandy M. S., Webb A. C., Auron P. E. 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. doi: 10.1093/nar/14.20.7897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cunningham B. C., Henner D. J., Wells J. A. Engineering human prolactin to bind to the human growth hormone receptor. Science. 1990 Mar 23;247(4949 Pt 1):1461–1465. doi: 10.1126/science.247.4949.1461. [DOI] [PubMed] [Google Scholar]
  9. Dinarello C. A. Biology of interleukin 1. FASEB J. 1988 Feb;2(2):108–115. [PubMed] [Google Scholar]
  10. Dower S. K., Kronheim S. R., Hopp T. P., Cantrell M., Deeley M., Gillis S., Henney C. S., Urdal D. L. The cell surface receptors for interleukin-1 alpha and interleukin-1 beta are identical. Nature. 1986 Nov 20;324(6094):266–268. doi: 10.1038/324266a0. [DOI] [PubMed] [Google Scholar]
  11. Eisenberg S. P., Evans R. J., Arend W. P., Verderber E., Brewer M. T., Hannum C. H., Thompson R. C. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990 Jan 25;343(6256):341–346. doi: 10.1038/343341a0. [DOI] [PubMed] [Google Scholar]
  12. Finzel B. C., Clancy L. L., Holland D. R., Muchmore S. W., Watenpaugh K. D., Einspahr H. M. Crystal structure of recombinant human interleukin-1 beta at 2.0 A resolution. J Mol Biol. 1989 Oct 20;209(4):779–791. doi: 10.1016/0022-2836(89)90606-2. [DOI] [PubMed] [Google Scholar]
  13. 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. doi: 10.1093/nar/14.8.3167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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. doi: 10.1093/nar/13.16.5869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gehrke L., Jobling S. A., Paik L. S., McDonald B., Rosenwasser L. J., Auron P. E. A point mutation uncouples human interleukin-1 beta biological activity and receptor binding. J Biol Chem. 1990 Apr 15;265(11):5922–5925. [PubMed] [Google Scholar]
  16. Graves B. J., Hatada M. H., Hendrickson W. A., Miller J. K., Madison V. S., Satow Y. Structure of interleukin 1 alpha at 2.7-A resolution. Biochemistry. 1990 Mar 20;29(11):2679–2684. doi: 10.1021/bi00463a009. [DOI] [PubMed] [Google Scholar]
  17. Gray P. W., Glaister D., Chen E., Goeddel D. V., 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] [Google Scholar]
  18. Hannum C. H., Wilcox C. J., Arend W. P., Joslin F. G., Dripps D. J., Heimdal P. L., Armes L. G., Sommer A., Eisenberg S. P., Thompson R. C. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. doi: 10.1038/343336a0. [DOI] [PubMed] [Google Scholar]
  19. Hazuda D. J., Strickler J., Kueppers F., Simon P. L., Young P. R. Processing of precursor interleukin 1 beta and inflammatory disease. J Biol Chem. 1990 Apr 15;265(11):6318–6322. [PubMed] [Google Scholar]
  20. Herrmann B. G., Frischauf A. M. Isolation of genomic DNA. Methods Enzymol. 1987;152:180–183. doi: 10.1016/0076-6879(87)52018-3. [DOI] [PubMed] [Google Scholar]
  21. Kilian P. L., Kaffka K. L., Stern A. S., Woehle D., Benjamin W. R., Dechiara T. M., Gubler U., Farrar J. J., Mizel S. B., Lomedico P. T. 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] [Google Scholar]
  22. Kobayashi Y., Yamamoto K., Saido T., Kawasaki H., Oppenheim J. J., 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. doi: 10.1073/pnas.87.14.5548. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kostura M. J., Tocci M. J., Limjuco G., Chin J., Cameron P., Hillman A. G., Chartrain N. A., Schmidt J. A. Identification of a monocyte specific pre-interleukin 1 beta convertase activity. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5227–5231. doi: 10.1073/pnas.86.14.5227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Larrick J. W. Native interleukin 1 inhibitors. Immunol Today. 1989 Feb;10(2):61–66. doi: 10.1016/0167-5699(89)90308-3. [DOI] [PubMed] [Google Scholar]
  25. Li W. H., Tanimura M., Sharp P. M. An evaluation of the molecular clock hypothesis using mammalian DNA sequences. J Mol Evol. 1987;25(4):330–342. doi: 10.1007/BF02603118. [DOI] [PubMed] [Google Scholar]
  26. Lomedico P. T., Gubler U., Hellmann C. P., Dukovich M., Giri J. G., Pan Y. C., Collier K., Semionow R., Chua A. O., Mizel S. B. Cloning and expression of murine interleukin-1 cDNA in Escherichia coli. 1984 Nov 29-Dec 5Nature. 312(5993):458–462. doi: 10.1038/312458a0. [DOI] [PubMed] [Google Scholar]
  27. Maliszewski C. R., Baker P. E., Schoenborn M. A., Davis B. S., Cosman D., Gillis S., Cerretti D. P. Cloning, sequence and expression of bovine interleukin 1 alpha and interleukin 1 beta complementary DNAs. Mol Immunol. 1988 May;25(5):429–437. doi: 10.1016/0161-5890(88)90162-9. [DOI] [PubMed] [Google Scholar]
  28. March C. J., Mosley B., Larsen A., Cerretti D. P., Braedt G., Price V., Gillis S., Henney C. S., Kronheim S. R., Grabstein K. Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature. 1985 Jun 20;315(6021):641–647. doi: 10.1038/315641a0. [DOI] [PubMed] [Google Scholar]
  29. Matsushima K., Akahoshi T., Yamada M., Furutani Y., Oppenheim J. J. 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] [Google Scholar]
  30. Maxam A. M., Gilbert W. A new method for sequencing DNA. Proc Natl Acad Sci U S A. 1977 Feb;74(2):560–564. doi: 10.1073/pnas.74.2.560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mollison K. W., Mandecki W., Zuiderweg E. R., Fayer L., Fey T. A., Krause R. A., Conway R. G., Miller L., Edalji R. P., Shallcross M. A. 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. doi: 10.1073/pnas.86.1.292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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. doi: 10.1016/0006-291x(88)90761-9. [DOI] [PubMed] [Google Scholar]
  33. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  34. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  36. Stetler G., Brewer M. T., Thompson R. C. Isolation and sequence of a human gene encoding a potent inhibitor of leukocyte proteases. Nucleic Acids Res. 1986 Oct 24;14(20):7883–7896. doi: 10.1093/nar/14.20.7883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Telford J. L., 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. doi: 10.1093/nar/14.24.9955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wood W. I. Gene cloning based on long oligonucleotide probes. Methods Enzymol. 1987;152:443–447. doi: 10.1016/0076-6879(87)52051-1. [DOI] [PubMed] [Google Scholar]
  39. Wyman A. R., Wertman K. F. Host strains that alleviate underrepresentation of specific sequences: overview. Methods Enzymol. 1987;152:173–180. doi: 10.1016/0076-6879(87)52017-1. [DOI] [PubMed] [Google Scholar]
  40. Young P. R., 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. doi: 10.1093/protein/2.7.545. [DOI] [PubMed] [Google Scholar]

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

RESOURCES