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. 1993 Sep;93(3):411–417. doi: 10.1111/j.1365-2249.1993.tb08193.x

C3 and C4 gene expression and interferon-gamma-mediated regulation in human glomerular mesangial cells.

S Sacks 1, W Zhou 1, R D Campbell 1, J Martin 1
PMCID: PMC1554924  PMID: 8370168

Abstract

The glomerular mesangial cell (GMC) plays a key role in the maintenance of glomerular structure and function and in the mediation of glomerular injury. To explore the potential of this cell to produce complement and react to local inflammatory signals, we studied the synthesis and regulation of the third and fourth components of complement in cultured human GMC. Using metabolic labelling and immunoprecipitation, we found that C3 and C4 polypeptide chains were synthesized and secreted by GMC. Interferon-gamma (IFN-gamma) led to an increase in C4 protein synthesis, but not C3 synthesis. There was a corresponding increase in C4 mRNA in IFN-gamma-activated cells, but no increase in C3 mRNA, as determined by semi-quantitative polymerase chain reaction (PCR) estimation. These results demonstrate that human GMC can synthesize C3 and C4 proteins, and that regulation of expression of the C4 gene is mediated by IFN-gamma. We hypothesize that GMC production of complement could influence the clearance of immune aggregates by the kidney and the mediation of glomerular injury.

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Selected References

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

  1. Abbott F., Ryan J. J., Ceska M., Matsushima K., Sarraf C. E., Rees A. J. Interleukin-1 beta stimulates human mesangial cells to synthesize and release interleukins-6 and -8. Kidney Int. 1991 Oct;40(4):597–605. doi: 10.1038/ki.1991.250. [DOI] [PubMed] [Google Scholar]
  2. Alper C. A., Johnson A. M., Birtch A. G., Moore F. D. Human C'3: evidence for the liver as the primary site of synthesis. Science. 1969 Jan 17;163(3864):286–288. doi: 10.1126/science.163.3864.286. [DOI] [PubMed] [Google Scholar]
  3. Belt K. T., Carroll M. C., Porter R. R. The structural basis of the multiple forms of human complement component C4. Cell. 1984 Apr;36(4):907–914. doi: 10.1016/0092-8674(84)90040-0. [DOI] [PubMed] [Google Scholar]
  4. Braun L., Schneider P. M., Giles C. M., Bertrams J., Rittner C. Null alleles of human complement C4. Evidence for pseudogenes at the C4A locus and for gene conversion at the C4B locus. J Exp Med. 1990 Jan 1;171(1):129–140. doi: 10.1084/jem.171.1.129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brooimans R. A., Stegmann A. P., van Dorp W. T., van der Ark A. A., van der Woude F. J., van Es L. A., Daha M. R. Interleukin 2 mediates stimulation of complement C3 biosynthesis in human proximal tubular epithelial cells. J Clin Invest. 1991 Aug;88(2):379–384. doi: 10.1172/JCI115314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Campbell R. D. The molecular genetics of components of the complement system. Baillieres Clin Rheumatol. 1988 Dec;2(3):547–575. doi: 10.1016/s0950-3579(88)80028-1. [DOI] [PubMed] [Google Scholar]
  7. Chan A. C., Atkinson J. P. Identification and structural characterization of two incompletely processed forms of the fourth component of human complement. J Clin Invest. 1983 Nov;72(5):1639–1649. doi: 10.1172/JCI111123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chelly J., Montarras D., Pinset C., Berwald-Netter Y., Kaplan J. C., Kahn A. Quantitative estimation of minor mRNAs by cDNA-polymerase chain reaction. Application to dystrophin mRNA in cultured myogenic and brain cells. Eur J Biochem. 1990 Feb 14;187(3):691–698. doi: 10.1111/j.1432-1033.1990.tb15355.x. [DOI] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Couser W. G., Baker P. J., Adler S. Complement and the direct mediation of immune glomerular injury: a new perspective. Kidney Int. 1985 Dec;28(6):879–890. doi: 10.1038/ki.1985.214. [DOI] [PubMed] [Google Scholar]
  11. Falus A. Regulation of complement biosynthesis by tissue-specific and hormonal factors. Immunol Lett. 1990 Jul;24(4):227–232. doi: 10.1016/0165-2478(90)90001-7. [DOI] [PubMed] [Google Scholar]
  12. Feucht H. E., Zwirner J., Bevec D., Lang M., Felber E., Riethmüller G., Weiss E. H. Biosynthesis of complement C4 messenger RNA in normal human kidney. Nephron. 1989;53(4):338–342. doi: 10.1159/000185778. [DOI] [PubMed] [Google Scholar]
  13. Fey G., Colten H. R. Biosynthesis of complement components. Fed Proc. 1981 May 15;40(7):2099–2104. [PubMed] [Google Scholar]
  14. Hawkins N. J., Wakefield D., Charlesworth J. A. The role of mesangial cells in glomerular pathology. Pathology. 1990 Jan;22(1):24–32. doi: 10.3109/00313029009061422. [DOI] [PubMed] [Google Scholar]
  15. KRAKOWER C. A., GREENSPON S. A. Factors leading to variation in concentration of nephrotoxic antigen(s) of glomerular basement membrane. AMA Arch Pathol. 1954 Nov;58(5):401–432. [PubMed] [Google Scholar]
  16. Katz Y., Cole F. S., Strunk R. C. Synergism between gamma interferon and lipopolysaccharide for synthesis of factor B, but not C2, in human fibroblasts. J Exp Med. 1988 Jan 1;167(1):1–14. doi: 10.1084/jem.167.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kester M., Simonson M. S., Mené P., Sedor J. R. Interleukin-1 generates transmembrane signals from phospholipids through novel pathways in cultured rat mesangial cells. J Clin Invest. 1989 Feb;83(2):718–723. doi: 10.1172/JCI113937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kinoshita T. Biology of complement: the overture. Immunol Today. 1991 Sep;12(9):291–295. doi: 10.1016/0167-5699(91)90001-A. [DOI] [PubMed] [Google Scholar]
  19. Knauss T. C., Mené P., Ricanati S. A., Kester M., Dubyak G. R., Emancipator S. N., Sedor J. R. Immune complex activation of rat glomerular mesangial cells: dependence on the Fc region of antibody. Am J Physiol. 1989 Sep;257(3 Pt 2):F478–F485. doi: 10.1152/ajprenal.1989.257.3.F478. [DOI] [PubMed] [Google Scholar]
  20. Kulics J., Colten H. R., Perlmutter D. H. Counterregulatory effects of interferon-gamma and endotoxin on expression of the human C4 genes. J Clin Invest. 1990 Mar;85(3):943–949. doi: 10.1172/JCI114523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  22. Lianos E. A. Eicosanoid biosynthesis and role in renal immune injury. Prostaglandins Leukot Essent Fatty Acids. 1990 Sep;41(1):1–12. doi: 10.1016/0952-3278(90)90124-4. [DOI] [PubMed] [Google Scholar]
  23. Mené P., Simonson M. S., Dunn M. J. Physiology of the mesangial cell. Physiol Rev. 1989 Oct;69(4):1347–1424. doi: 10.1152/physrev.1989.69.4.1347. [DOI] [PubMed] [Google Scholar]
  24. Miura N., Prentice H. L., Schneider P. M., Perlmutter D. H. Synthesis and regulation of the two human complement C4 genes in stable transfected mouse fibroblasts. J Biol Chem. 1987 May 25;262(15):7298–7305. [PubMed] [Google Scholar]
  25. Noonan K. E., Beck C., Holzmayer T. A., Chin J. E., Wunder J. S., Andrulis I. L., Gazdar A. F., Willman C. L., Griffith B., Von Hoff D. D. Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7160–7164. doi: 10.1073/pnas.87.18.7160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Passwell J., Schreiner G. F., Nonaka M., Beuscher H. U., Colten H. R. Local extrahepatic expression of complement genes C3, factor B, C2, and C4 is increased in murine lupus nephritis. J Clin Invest. 1988 Nov;82(5):1676–1684. doi: 10.1172/JCI113780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ponte P., Ng S. Y., Engel J., Gunning P., Kedes L. Evolutionary conservation in the untranslated regions of actin mRNAs: DNA sequence of a human beta-actin cDNA. Nucleic Acids Res. 1984 Feb 10;12(3):1687–1696. doi: 10.1093/nar/12.3.1687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ripoche J., Mitchell J. A., Erdei A., Madin C., Moffatt B., Mokoena T., Gordon S., Sim R. B. Interferon gamma induces synthesis of complement alternative pathway proteins by human endothelial cells in culture. J Exp Med. 1988 Nov 1;168(5):1917–1922. doi: 10.1084/jem.168.5.1917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ruddy S., Colten H. R. Rheumatoid arthritis. Biosynthesis of complement proteins by synovial tissues. N Engl J Med. 1974 Jun 6;290(23):1284–1288. doi: 10.1056/NEJM197406062902304. [DOI] [PubMed] [Google Scholar]
  30. Schifferli J. A., Ng Y. C., Peters D. K. The role of complement and its receptor in the elimination of immune complexes. N Engl J Med. 1986 Aug 21;315(8):488–495. doi: 10.1056/NEJM198608213150805. [DOI] [PubMed] [Google Scholar]
  31. Schönermark M., Deppisch R., Riedasch G., Rother K., Hänsch G. M. Induction of mediator release from human glomerular mesangial cells by the terminal complement components C5b-9. Int Arch Allergy Appl Immunol. 1991;96(4):331–337. doi: 10.1159/000235517. [DOI] [PubMed] [Google Scholar]
  32. Strunk R. C., Cole F. S., Perlmutter D. H., Colten H. R. gamma-Interferon increases expression of class III complement genes C2 and factor B in human monocytes and in murine fibroblasts transfected with human C2 and factor B genes. J Biol Chem. 1985 Dec 5;260(28):15280–15285. [PubMed] [Google Scholar]
  33. Strunk R. C., Whitehead A. S., Cole F. S. Pretranslational regulation of the synthesis of the third component of complement in human mononuclear phagocytes by the lipid A portion of lipopolysaccharide. J Clin Invest. 1985 Sep;76(3):985–990. doi: 10.1172/JCI112099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Topley N., Floege J., Wessel K., Hass R., Radeke H. H., Kaever V., Resch K. Prostaglandin E2 production is synergistically increased in cultured human glomerular mesangial cells by combinations of IL-1 and tumor necrosis factor-alpha 1. J Immunol. 1989 Sep 15;143(6):1989–1995. [PubMed] [Google Scholar]
  35. Veis J. H., Yamashita W., Liu Y. J., Ooi B. S. The biology of mesangial cells in glomerulonephritis. Proc Soc Exp Biol Med. 1990 Nov;195(2):160–167. doi: 10.3181/00379727-195-43129a. [DOI] [PubMed] [Google Scholar]
  36. Whaley K. Biosynthesis of the complement components and the regulatory proteins of the alternative complement pathway by human peripheral blood monocytes. J Exp Med. 1980 Mar 1;151(3):501–516. doi: 10.1084/jem.151.3.501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Witte D. P., Welch T. R., Beischel L. S. Detection and cellular localization of human C4 gene expression in the renal tubular epithelial cells and other extrahepatic epithelial sources. Am J Pathol. 1991 Oct;139(4):717–724. [PMC free article] [PubMed] [Google Scholar]
  38. de Bruijn M. H., Fey G. H. Human complement component C3: cDNA coding sequence and derived primary structure. Proc Natl Acad Sci U S A. 1985 Feb;82(3):708–712. doi: 10.1073/pnas.82.3.708. [DOI] [PMC free article] [PubMed] [Google Scholar]

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