Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1990 Mar;85(3):943–949. doi: 10.1172/JCI114523

Counterregulatory effects of interferon-gamma and endotoxin on expression of the human C4 genes.

J Kulics 1, H R Colten 1, D H Perlmutter 1
PMCID: PMC296514  PMID: 2107212

Abstract

Susceptibility to autoimmune disease is associated with null alleles at one of the two genetic loci encoding complement protein C4. These two genetic loci, C4A and C4B, are highly homologous in primary structure but encode proteins with different functional activities. Expression of C4A and C4B genes is regulated by IFN-gamma in human hepatoma cells and in murine fibroblasts transformed with the respective genes. In these cell lines, IFN-gamma has a significantly greater and longer-lasting effect on expression of C4A than that of C4B. In this study we examined synthesis and regulation of C4A and C4B in peripheral blood monocytes from normal, C4A-null, and C4B-null individuals. Synthesis of C4 in human peripheral blood monocytes decreases during time in culture. IFN-gamma mediates a concentration- and time-dependent increase in steady-state levels of C4 mRNA and a corresponding increase in synthesis of C4 in normal human monocytes. LPS decreases monocyte C4 expression and completely abrogates the effect of IFN-gamma on the expression of this gene. In contrast, LPS and IFN-gamma have a synergistic effect in upregulating expression of another class III MHC gene product, complement protein factor B. The effect of LPS on constitutive and IFN-gamma-regulated C4 synthesis is probably not mediated via release of endogenous monokines IL-1 beta, TNF-alpha, or IL-6. Synthesis of C4, and regulation of its synthesis by IFN-gamma and LPS, are similar in normal, C4A-, and C4B-null individuals. These results demonstrate the synthesis of C4 at extrahepatic sites and tissue-specific regulation of C4 gene expression.

Full text

PDF
943

Images in this article

944Image
on p.944
944Image
on p.944
945Image
on p.945
945Image
on p.945
945Image
on p.945
946Image
on p.946
946Image
on p.946
946Image
on p.946
946Image
on p.946
947Image
on p.947
947Image
on p.947
947Image
on p.947

Selected References

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

  1. Awdeh Z. L., Alper C. A. Inherited structural polymorphism of the fourth component of human complement. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3576–3580. doi: 10.1073/pnas.77.6.3576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barbey-Morel C., Pierce J. A., Campbell E. J., Perlmutter D. H. Lipopolysaccharide modulates the expression of alpha 1 proteinase inhibitor and other serine proteinase inhibitors in human monocytes and macrophages. J Exp Med. 1987 Oct 1;166(4):1041–1054. doi: 10.1084/jem.166.4.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bell G. I., Karam J. H., Rutter W. J. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5759–5763. doi: 10.1073/pnas.78.9.5759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Belt K. T., Yu C. Y., Carroll M. C., Porter R. R. Polymorphism of human complement component C4. Immunogenetics. 1985;21(2):173–180. doi: 10.1007/BF00364869. [DOI] [PubMed] [Google Scholar]
  6. Carroll M. C., Belt T., Palsdottir A., Porter R. R. Structure and organization of the C4 genes. Philos Trans R Soc Lond B Biol Sci. 1984 Sep 6;306(1129):379–388. doi: 10.1098/rstb.1984.0098. [DOI] [PubMed] [Google Scholar]
  7. Carroll M. C., Campbell R. D., Bentley D. R., Porter R. R. A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B. Nature. 1984 Jan 19;307(5948):237–241. doi: 10.1038/307237a0. [DOI] [PubMed] [Google Scholar]
  8. Carroll M. C., Campbell R. D., Porter R. R. Mapping of steroid 21-hydroxylase genes adjacent to complement component C4 genes in HLA, the major histocompatibility complex in man. Proc Natl Acad Sci U S A. 1985 Jan;82(2):521–525. doi: 10.1073/pnas.82.2.521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Carroll M. C., Palsdottir A., Belt K. T., Porter R. R. Deletion of complement C4 and steroid 21-hydroxylase genes in the HLA class III region. EMBO J. 1985 Oct;4(10):2547–2552. doi: 10.1002/j.1460-2075.1985.tb03969.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Chaplin D. D., Woods D. E., Whitehead A. S., Goldberger G., Colten H. R., Seidman J. G. Molecular map of the murine S region. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6947–6951. doi: 10.1073/pnas.80.22.6947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  13. Cole F. S., Auerbach H. S., Goldberger G., Colten H. R. Tissue-specific pretranslational regulation of complement production in human mononuclear phagocytes. J Immunol. 1985 Apr;134(4):2610–2616. [PubMed] [Google Scholar]
  14. Isenman D. E., Young J. R. The molecular basis for the difference in immune hemolysis activity of the Chido and Rodgers isotypes of human complement component C4. J Immunol. 1984 Jun;132(6):3019–3027. [PubMed] [Google Scholar]
  15. 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]
  16. Kemp M. E., Atkinson J. P., Skanes V. M., Levine R. P., Chaplin D. D. Deletion of C4A genes in patients with systemic lupus erythematosus. Arthritis Rheum. 1987 Sep;30(9):1015–1022. doi: 10.1002/art.1780300908. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Law S. K., Dodds A. W., Porter R. R. A comparison of the properties of two classes, C4A and C4B, of the human complement component C4. EMBO J. 1984 Aug;3(8):1819–1823. doi: 10.1002/j.1460-2075.1984.tb02052.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Newell S. L., Shreffler D. C., Atkinson J. P. Biosynthesis of C4 by mouse peritoneal macrophages. I. Characterization of an in vitro culture system and comparison of C4 synthesis by "low" vs "high" C4 strains. J Immunol. 1982 Aug;129(2):653–659. [PubMed] [Google Scholar]
  22. Partanen J., Peltonen L., Koskimies S., Carroll M. C. DNA polymorphism of human HLA-linked complement C4 allotypes, including C4 null alleles, in the Finnish population. Hum Hered. 1987;37(4):241–249. doi: 10.1159/000153711. [DOI] [PubMed] [Google Scholar]
  23. Passmore H. C., Shreffler D. C. A sex-limited serum protein variant in the mouse: inheritance and association with the H-2 region. Biochem Genet. 1970 Jun;4(3):351–365. doi: 10.1007/BF00485752. [DOI] [PubMed] [Google Scholar]
  24. Perlmutter D. H., Colten H. R. Structure and expression of the complement genes. Pharmacol Ther. 1987;34(2):247–270. doi: 10.1016/0163-7258(87)90013-1. [DOI] [PubMed] [Google Scholar]
  25. Roberts B. E., Paterson B. M. Efficient translation of tobacco mosaic virus RNA and rabbit globin 9S RNA in a cell-free system from commercial wheat germ. Proc Natl Acad Sci U S A. 1973 Aug;70(8):2330–2334. doi: 10.1073/pnas.70.8.2330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sackstein R., Colten H. R. Molecular regulation of MHC class III (C4 and factor B) gene expression in mouse peritoneal macrophages. J Immunol. 1984 Sep;133(3):1618–1626. [PubMed] [Google Scholar]
  27. 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]
  28. 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]
  29. Schneider P. M., Carroll M. C., Alper C. A., Rittner C., Whitehead A. S., Yunis E. J., Colten H. R. Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants. J Clin Invest. 1986 Sep;78(3):650–657. doi: 10.1172/JCI112623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shreffler D. C., Atkinson J. P., Chan A. C., Karp D. R., Killion C. C., Ogata R. T., Rosa P. A. The C4 and Slp genes of the complement region of the murine H-2 major histocompatibility complex. Philos Trans R Soc Lond B Biol Sci. 1984 Sep 6;306(1129):395–403. doi: 10.1098/rstb.1984.0100. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Stecher V. J., Morse J. H., Thorbecke G. J. Sites of production of primate serum proteins associated with complement system. Proc Soc Exp Biol Med. 1967 Feb;124(2):433–438. doi: 10.3181/00379727-124-31758. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Sztein M. B., Steeg P. S., Johnson H. M., Oppenheim J. J. Regulation of human peripheral blood monocyte DR antigen expression in vitro by lymphokines and recombinant interferons. J Clin Invest. 1984 Feb;73(2):556–565. doi: 10.1172/JCI111243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Uring-Lambert B., Vegnaduzzi N., Carroll M. C., Tongio M. M., Goetz J., Hauptmann G. Heterogeneity in the structural basis of the human complement C4A null allele (C4A Q0) as revealed by HindIII restriction fragment length polymorphism analysis. FEBS Lett. 1987 Jun 8;217(1):65–68. doi: 10.1016/0014-5793(87)81244-9. [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. White P. C., Grossberger D., Onufer B. J., Chaplin D. D., New M. I., Dupont B., Strominger J. L. Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man. Proc Natl Acad Sci U S A. 1985 Feb;82(4):1089–1093. doi: 10.1073/pnas.82.4.1089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Whitehead A. S., Goldberger G., Woods D. E., Markham A. F., Colten H. R. Use of a cDNA clone for the fourth component of human complement (C4) for analysis of a genetic deficiency of C4 in guinea pig. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5387–5391. doi: 10.1073/pnas.80.17.5387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yu C. Y., Campbell R. D. Definitive RFLPs to distinguish between the human complement C4A/C4B isotypes and the major Rodgers/Chido determinants: application to the study of C4 null alleles. Immunogenetics. 1987;25(6):383–390. doi: 10.1007/BF00396104. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES