Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1994 Jul;145(1):126–136.

Glomerular expression of interleukin-1 receptor antagonist and interleukin-1 beta genes in antibody-mediated glomerulonephritis.

F W Tam 1, J Smith 1, S J Cashman 1, Y Wang 1, E M Thompson 1, A J Rees 1
PMCID: PMC1887310  PMID: 8030744

Abstract

Interleukin-1 (IL-1) is a powerful proinflammatory cytokine whose function is modulated by a natural IL-1 receptor antagonist (IL-1ra). There are few data about kinetics of in vivo synthesis of IL-1ra at tissue level, except in response to bacterial endotoxin. The purpose of this study was to examine the kinetics of local expression of IL-1ra gene in relation to IL-1 beta gene in a model of anti-glomerular basement membrane antibody-mediated glomerulonephritis. Rats were killed in groups of 5 or 6 at 0, 4, 6, 24, 48, and 96 hours after induction of glomerulonephritis. Messenger RNA for IL-1ra and IL-1 beta was undetectable by Northern blot in normal glomeruli but increased markedly 4 to 6 hours after induction of nephritis. The increase in IL-1ra mRNA was more sustained than that of IL-1 beta mRNA. In situ hybridization showed that IL-1 beta mRNA increased diffusely within glomeruli, while IL-1ra mRNA was expressed more discretely. Expression of these mRNA in noninflamed tissues, spleens and lungs, was different, particularly increase in IL-1ra mRNA was more substantial than that of IL-1 beta. These observations suggest that differential expression of IL-1ra and IL-1 beta might focus inflammation in glomeruli while protecting more distant sites. They also raise the possibility of reducing glomerular injury by therapeutic measures that upregulate glomerular synthesis of IL-1ra while reducing that of IL-1 beta.

Full text

PDF
126

Images in this article

130Figure 1
on p.130
130Figure 2
on p.130
132Figure 4
on p.132
133Figure 5
on p.133

Selected References

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

  1. Abbott F., Tam F. W., Ryan J. J., Rees A. J. Human mesangial cells synthesize interleukin 1 alpha but not interleukin 1 beta, interleukin 1 receptor antagonist, or tumour necrosis factor. Nephrol Dial Transplant. 1992;7(10):997–1001. [PubMed] [Google Scholar]
  2. Alexander H. R., Doherty G. M., Buresh C. M., Venzon D. J., Norton J. A. A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J Exp Med. 1991 Apr 1;173(4):1029–1032. doi: 10.1084/jem.173.4.1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. An S. F., Franklin D., Fleming K. A. Generation of digoxigenin-labelled double-stranded and single-stranded probes using the polymerase chain reaction. Mol Cell Probes. 1992 Jun;6(3):193–200. doi: 10.1016/0890-8508(92)90016-q. [DOI] [PubMed] [Google Scholar]
  4. Arend W. P., Smith M. F., Jr, Janson R. W., Joslin F. G. IL-1 receptor antagonist and IL-1 beta production in human monocytes are regulated differently. J Immunol. 1991 Sep 1;147(5):1530–1536. [PubMed] [Google Scholar]
  5. Boswell J. M., Yui M. A., Burt D. W., Kelley V. E. Increased tumor necrosis factor and IL-1 beta gene expression in the kidneys of mice with lupus nephritis. J Immunol. 1988 Nov 1;141(9):3050–3054. [PubMed] [Google Scholar]
  6. Burchett S. K., Weaver W. M., Westall J. A., Larsen A., Kronheim S., Wilson C. B. Regulation of tumor necrosis factor/cachectin and IL-1 secretion in human mononuclear phagocytes. J Immunol. 1988 May 15;140(10):3473–3481. [PubMed] [Google Scholar]
  7. Chan L. S., Hammerberg C., Kang K., Sabb P., Tavakkol A., Cooper K. D. Human dermal fibroblast interleukin-1 receptor antagonist (IL-1ra) and interleukin-1 beta (IL-1 beta) mRNA and protein are co-stimulated by phorbol ester: implication for a homeostatic mechanism. J Invest Dermatol. 1992 Sep;99(3):315–322. doi: 10.1111/1523-1747.ep12616653. [DOI] [PubMed] [Google Scholar]
  8. Chan V. T., Fleming K. A., McGee J. O. Detection of sub-picogram quantities of specific DNA sequences on blot hybridization with biotinylated probes. Nucleic Acids Res. 1985 Nov 25;13(22):8083–8091. doi: 10.1093/nar/13.22.8083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chantry D., Turner M., Abney E., Feldmann M. Modulation of cytokine production by transforming growth factor-beta. J Immunol. 1989 Jun 15;142(12):4295–4300. [PubMed] [Google Scholar]
  10. Chensue S. W., Bienkowski M., Eessalu T. E., Warmington K. S., Hershey S. D., Lukacs N. W., Kunkel S. L. Endogenous IL-1 receptor antagonist protein (IRAP) regulates schistosome egg granuloma formation and the regional lymphoid response. J Immunol. 1993 Oct 1;151(7):3654–3662. [PubMed] [Google Scholar]
  11. Cowan N. J., Dobner P. R., Fuchs E. V., Cleveland D. W. Expression of human alpha-tubulin genes: interspecies conservation of 3' untranslated regions. Mol Cell Biol. 1983 Oct;3(10):1738–1745. doi: 10.1128/mcb.3.10.1738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dijkstra C. D., Döpp E. A., Joling P., Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology. 1985 Mar;54(3):589–599. [PMC free article] [PubMed] [Google Scholar]
  13. Dinarello C. A., Thompson R. C. Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today. 1991 Nov;12(11):404–410. doi: 10.1016/0167-5699(91)90142-G. [DOI] [PubMed] [Google Scholar]
  14. Dinarello C. A., Wolff S. M. The role of interleukin-1 in disease. N Engl J Med. 1993 Jan 14;328(2):106–113. doi: 10.1056/NEJM199301143280207. [DOI] [PubMed] [Google Scholar]
  15. Eisenberg S. P., Brewer M. T., Verderber E., Heimdal P., Brandhuber B. J., Thompson R. C. Interleukin 1 receptor antagonist is a member of the interleukin 1 gene family: evolution of a cytokine control mechanism. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5232–5236. doi: 10.1073/pnas.88.12.5232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. El Nahas A. M., Lechler R., Zoob S. N., Rees A. J. Progression to renal failure after nephrotoxic nephritis in rats studied by renal transplantation. Clin Sci (Lond) 1985 Jan;68(1):15–21. doi: 10.1042/cs0680015. [DOI] [PubMed] [Google Scholar]
  18. Firestein G. S., Berger A. E., Tracey D. E., Chosay J. G., Chapman D. L., Paine M. M., Yu C., Zvaifler N. J. IL-1 receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium. J Immunol. 1992 Aug 1;149(3):1054–1062. [PubMed] [Google Scholar]
  19. Fischer E., Marano M. A., Van Zee K. J., Rock C. S., Hawes A. S., Thompson W. A., DeForge L., Kenney J. S., Remick D. G., Bloedow D. C. Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. J Clin Invest. 1992 May;89(5):1551–1557. doi: 10.1172/JCI115748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fischer E., Van Zee K. J., Marano M. A., Rock C. S., Kenney J. S., Poutsiaka D. D., Dinarello C. A., Lowry S. F., Moldawer L. L. Interleukin-1 receptor antagonist circulates in experimental inflammation and in human disease. Blood. 1992 May 1;79(9):2196–2200. [PubMed] [Google Scholar]
  21. Fleming K. A., Evans M., Ryley K. C., Franklin D., Lovell-Badge R. H., Morey A. L. Optimization of non-isotopic in situ hybridization on formalin-fixed, paraffin-embedded material using digoxigenin-labelled probes and transgenic tissues. J Pathol. 1992 May;167(1):9–17. doi: 10.1002/path.1711670104. [DOI] [PubMed] [Google Scholar]
  22. Granowitz E. V., Santos A. A., Poutsiaka D. D., Cannon J. G., Wilmore D. W., Wolff S. M., Dinarello C. A. Production of interleukin-1-receptor antagonist during experimental endotoxaemia. Lancet. 1991 Dec 7;338(8780):1423–1424. doi: 10.1016/0140-6736(91)92725-h. [DOI] [PubMed] [Google Scholar]
  23. Granstein R. D., Margolis R., Mizel S. B., Sauder D. N. In vivo inflammatory activity of epidermal cell-derived thymocyte activating factor and recombinant interleukin 1 in the mouse. J Clin Invest. 1986 Mar;77(3):1020–1027. doi: 10.1172/JCI112354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hogquist K. A., Nett M. A., Unanue E. R., Chaplin D. D. Interleukin 1 is processed and released during apoptosis. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8485–8489. doi: 10.1073/pnas.88.19.8485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Isaacs K. L., Sartor R. B., Haskill S. Cytokine messenger RNA profiles in inflammatory bowel disease mucosa detected by polymerase chain reaction amplification. Gastroenterology. 1992 Nov;103(5):1587–1595. doi: 10.1016/0016-5085(92)91182-4. [DOI] [PubMed] [Google Scholar]
  26. Karkar A. M., Koshino Y., Cashman S. J., Dash A. C., Bonnefoy J., Meager A., Rees A. J. Passive immunization against tumour necrosis factor-alpha (TNF-alpha) and IL-1 beta protects from LPS enhancing glomerular injury in nephrotoxic nephritis in rats. Clin Exp Immunol. 1992 Nov;90(2):312–318. doi: 10.1111/j.1365-2249.1992.tb07948.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Karkar A. M., Tam F. W., Proudfoot A. E., Meager A., Rees A. J. Modulation of antibody-mediated glomerular injury in vivo by interleukin-6. Kidney Int. 1993 Nov;44(5):967–973. doi: 10.1038/ki.1993.338. [DOI] [PubMed] [Google Scholar]
  28. Lan H. Y., Nikolic-Paterson D. J., Zarama M., Vannice J. L., Atkins R. C. Suppression of experimental crescentic glomerulonephritis by the interleukin-1 receptor antagonist. Kidney Int. 1993 Feb;43(2):479–485. doi: 10.1038/ki.1993.70. [DOI] [PubMed] [Google Scholar]
  29. MacDonald R. J., Swift G. H., Przybyla A. E., Chirgwin J. M. Isolation of RNA using guanidinium salts. Methods Enzymol. 1987;152:219–227. doi: 10.1016/0076-6879(87)52023-7. [DOI] [PubMed] [Google Scholar]
  30. Marucha P. T., Zeff R. A., Kreutzer D. L. Cytokine regulation of IL-1 beta gene expression in the human polymorphonuclear leukocyte. J Immunol. 1990 Nov 1;145(9):2932–2937. [PubMed] [Google Scholar]
  31. Matsukawa A., Ohkawara S., Maeda T., Takagi K., Yoshinaga M. Production of IL-1 and IL-1 receptor antagonist and the pathological significance in lipopolysaccharide-induced arthritis in rabbits. Clin Exp Immunol. 1993 Aug;93(2):206–211. doi: 10.1111/j.1365-2249.1993.tb07967.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Matsumoto K., Dowling J., Atkins R. C. Production of interleukin 1 in glomerular cell cultures from patients with rapidly progressive crescentic glomerulonephritis. Am J Nephrol. 1988;8(6):463–470. doi: 10.1159/000167656. [DOI] [PubMed] [Google Scholar]
  33. Matsumoto K., Hatano M. Production of interleukin 1 in glomerular cell cultures from rats with nephrotoxic serum nephritis. Clin Exp Immunol. 1989 Jan;75(1):123–128. [PMC free article] [PubMed] [Google Scholar]
  34. Miller L. C., Lynch E. A., Isa S., Logan J. W., Dinarello C. A., Steere A. C. Balance of synovial fluid IL-1 beta and IL-1 receptor antagonist and recovery from Lyme arthritis. Lancet. 1993 Jan 16;341(8838):146–148. doi: 10.1016/0140-6736(93)90006-3. [DOI] [PubMed] [Google Scholar]
  35. Ohlsson K., Björk P., Bergenfeldt M., Hageman R., Thompson R. C. Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature. 1990 Dec 6;348(6301):550–552. doi: 10.1038/348550a0. [DOI] [PubMed] [Google Scholar]
  36. Poutsiaka D. D., Clark B. D., Vannier E., Dinarello C. A. Production of interleukin-1 receptor antagonist and interleukin-1 beta by peripheral blood mononuclear cells is differentially regulated. Blood. 1991 Sep 1;78(5):1275–1281. [PubMed] [Google Scholar]
  37. Schindler R., Mancilla J., Endres S., Ghorbani R., Clark S. C., Dinarello C. A. 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. Blood. 1990 Jan 1;75(1):40–47. [PubMed] [Google Scholar]
  38. Sedor J. R., Nakazato Y., Konieczkowski M. Interleukin-1 and the mesangial cell. Kidney Int. 1992 Mar;41(3):595–599. doi: 10.1038/ki.1992.89. [DOI] [PubMed] [Google Scholar]
  39. Thornberry N. A., Bull H. G., Calaycay J. R., Chapman K. T., Howard A. D., Kostura M. J., Miller D. K., Molineaux S. M., Weidner J. R., Aunins J. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992 Apr 30;356(6372):768–774. doi: 10.1038/356768a0. [DOI] [PubMed] [Google Scholar]
  40. Tipping P. G., Lowe M. G., Holdsworth S. R. Glomerular interleukin 1 production is dependent on macrophage infiltration in anti-GBM glomerulonephritis. Kidney Int. 1991 Jan;39(1):103–110. doi: 10.1038/ki.1991.13. [DOI] [PubMed] [Google Scholar]
  41. Tomosugi N. I., Cashman S. J., Hay H., Pusey C. D., Evans D. J., Shaw A., Rees A. J. Modulation of antibody-mediated glomerular injury in vivo by bacterial lipopolysaccharide, tumor necrosis factor, and IL-1. J Immunol. 1989 May 1;142(9):3083–3090. [PubMed] [Google Scholar]
  42. Ulich T. R., Guo K. Z., Remick D., del Castillo J., Yin S. M. Endotoxin-induced cytokine gene expression in vivo. III. IL-6 mRNA and serum protein expression and the in vivo hematologic effects of IL-6. J Immunol. 1991 Apr 1;146(7):2316–2323. [PubMed] [Google Scholar]
  43. Ulich T. R., Guo K., Yin S., del Castillo J., Yi E. S., Thompson R. C., Eisenberg S. P. Endotoxin-induced cytokine gene expression in vivo. IV. Expression of interleukin-1 alpha/beta and interleukin-1 receptor antagonist mRNA during endotoxemia and during endotoxin-initiated local acute inflammation. Am J Pathol. 1992 Jul;141(1):61–68. [PMC free article] [PubMed] [Google Scholar]
  44. Ulich T. R., Yin S. M., Guo K. Z., del Castillo J., Eisenberg S. P., Thompson R. C. The intratracheal administration of endotoxin and cytokines. III. The interleukin-1 (IL-1) receptor antagonist inhibits endotoxin- and IL-1-induced acute inflammation. Am J Pathol. 1991 Mar;138(3):521–524. [PMC free article] [PubMed] [Google Scholar]
  45. Ulich T. R., Yin S., Guo K., Yi E. S., Remick D., del Castillo J. Intratracheal injection of endotoxin and cytokines. II. Interleukin-6 and transforming growth factor beta inhibit acute inflammation. Am J Pathol. 1991 May;138(5):1097–1101. [PMC free article] [PubMed] [Google Scholar]
  46. Werber H. I., Emancipator S. N., Tykocinski M. L., Sedor J. R. The interleukin 1 gene is expressed by rat glomerular mesangial cells and is augmented in immune complex glomerulonephritis. J Immunol. 1987 May 15;138(10):3207–3212. [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES