Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1999 Oct;107(Suppl 5):807–810. doi: 10.1289/ehp.99107s5807

Cytokine regulation of a rodent model of mercuric chloride-induced autoimmunity.

L M Bagenstose 1, P Salgame 1, M Monestier 1
PMCID: PMC1566235  PMID: 10502547

Abstract

Experimental models of chemically induced autoimmunity have contributed to our understanding of the development of autoimmune diseases in humans. Heavy metals such as mercury induce a dramatic activation of the immune system and autoantibody production in genetically susceptible rats and mice. This autoimmune syndrome is dependent on T cells, which are important for B-cell activation and cytokine secretion. Several studies have focused on the roles of T-helper (Th)1 and Th2 cells and their respective cytokines in the pathogenesis of mercury-induced disease. This article reviews recent studies that have examined the patterns of cytokine gene expression and where investigators have manipulated the Th1 and Th2 responses that occur during mercury-induced autoimmunity. Finally, we will discuss some biochemical/molecular mechanisms by which heavy metals may induce cytokine gene expression.

Full text

PDF
809

Selected References

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

  1. Aten J., Veninga A., Coers W., Sonnenberg A., Timpl R., Claessen N., van Eendenburg J. D., de Heer E., Weening J. J. Autoantibodies to the laminin P1 fragment in HgCl2-induced membranous glomerulopathy. Am J Pathol. 1995 Jun;146(6):1467–1480. [PMC free article] [PubMed] [Google Scholar]
  2. Aten J., Veninga A., De Heer E., Rozing J., Nieuwenhuis P., Hoedemaeker P. J., Weening J. J. Susceptibility to the induction of either autoimmunity or immunosuppression by mercuric chloride is related to the major histocompatibility complex class II haplotype. Eur J Immunol. 1991 Mar;21(3):611–616. doi: 10.1002/eji.1830210312. [DOI] [PubMed] [Google Scholar]
  3. Badou A., Savignac M., Moreau M., Leclerc C., Pasquier R., Druet P., Pelletier L. HgCl2-induced interleukin-4 gene expression in T cells involves a protein kinase C-dependent calcium influx through L-type calcium channels. J Biol Chem. 1997 Dec 19;272(51):32411–32418. doi: 10.1074/jbc.272.51.32411. [DOI] [PubMed] [Google Scholar]
  4. Bagenstose L. M., Salgame P., Monestier M. IL-12 down-regulates autoantibody production in mercury-induced autoimmunity. J Immunol. 1998 Feb 15;160(4):1612–1617. [PubMed] [Google Scholar]
  5. Bagenstose L. M., Salgame P., Monestier M. Mercury-induced autoimmunity in the absence of IL-4. Clin Exp Immunol. 1998 Oct;114(1):9–12. doi: 10.1046/j.1365-2249.1998.00704.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bretscher P. A., Wei G., Menon J. N., Bielefeldt-Ohmann H. Establishment of stable, cell-mediated immunity that makes "susceptible" mice resistant to Leishmania major. Science. 1992 Jul 24;257(5069):539–542. doi: 10.1126/science.1636090. [DOI] [PubMed] [Google Scholar]
  7. Bridoux F., Badou A., Saoudi A., Bernard I., Druet E., Pasquier R., Druet P., Pelletier L. Transforming growth factor beta (TGF-beta)-dependent inhibition of T helper cell 2 (Th2)-induced autoimmunity by self-major histocompatibility complex (MHC) class II-specific, regulatory CD4(+) T cell lines. J Exp Med. 1997 May 19;185(10):1769–1775. doi: 10.1084/jem.185.10.1769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Castedo M., Pelletier L., Pasquier R., Druet P. Improvement of TH1 functions during the regulation phase of mercury disease in brown Norway rats. Scand J Immunol. 1994 Feb;39(2):144–150. doi: 10.1111/j.1365-3083.1994.tb03353.x. [DOI] [PubMed] [Google Scholar]
  9. Doth M., Fricke M., Nicoletti F., Garotta G., Van Velthuysen M. L., Bruijn J. A., Gleichmann E. Genetic differences in immune reactivity to mercuric chloride (HgCl2): immunosuppression of H-2d mice is mediated by interferon-gamma (IFN-gamma). Clin Exp Immunol. 1997 Jul;109(1):149–156. doi: 10.1046/j.1365-2249.1997.4041300.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Druet P., Teychenne P., Mandet C., Bascou C., Druet E. Immune-type glomerulonephritis induced in the Brown-Norway rat with mercury-containing pharmaceutical products. Nephron. 1981;28(3):145–148. doi: 10.1159/000182136. [DOI] [PubMed] [Google Scholar]
  11. Eneström S., Hultman P. Does amalgam affect the immune system? A controversial issue. Int Arch Allergy Immunol. 1995 Mar;106(3):180–203. doi: 10.1159/000236843. [DOI] [PubMed] [Google Scholar]
  12. Gajewski T. F., Schell S. R., Fitch F. W. Evidence implicating utilization of different T cell receptor-associated signaling pathways by TH1 and TH2 clones. J Immunol. 1990 Jun 1;144(11):4110–4120. [PubMed] [Google Scholar]
  13. Germann T., Guckes S., Bongartz M., Dlugonska H., Schmitt E., Kolbe L., Kölsch E., Podlaski F. J., Gately M. K., Rüde E. Administration of IL-12 during ongoing immune responses fails to permanently suppress and can even enhance the synthesis of antigen-specific IgE. Int Immunol. 1995 Oct;7(10):1649–1657. doi: 10.1093/intimm/7.10.1649. [DOI] [PubMed] [Google Scholar]
  14. Gillespie K. M., Saoudi A., Kuhn J., Whittle C. J., Druet P., Bellon B., Mathieson P. W. Th1/Th2 cytokine gene expression after mercuric chloride in susceptible and resistant rat strains. Eur J Immunol. 1996 Oct;26(10):2388–2392. doi: 10.1002/eji.1830261018. [DOI] [PubMed] [Google Scholar]
  15. Goldman M., Druet P., Gleichmann E. TH2 cells in systemic autoimmunity: insights from allogeneic diseases and chemically-induced autoimmunity. Immunol Today. 1991 Jul;12(7):223–227. doi: 10.1016/0167-5699(91)90034-Q. [DOI] [PubMed] [Google Scholar]
  16. Griem P., Gleichmann E. Metal ion induced autoimmunity. Curr Opin Immunol. 1995 Dec;7(6):831–838. doi: 10.1016/0952-7915(95)80056-5. [DOI] [PubMed] [Google Scholar]
  17. Hanley G. A., Schiffenbauer J., Sobel E. S. Class II haplotype differentially regulates immune response in HgCl2-treated mice. Clin Immunol Immunopathol. 1997 Sep;84(3):328–337. doi: 10.1006/clin.1997.4405. [DOI] [PubMed] [Google Scholar]
  18. Hanley G. A., Schiffenbauer J., Sobel E. S. Resistance to HgCl2-induced autoimmunity in haplotype-heterozygous mice is an intrinsic property of B cells. J Immunol. 1998 Aug 15;161(4):1778–1785. [PubMed] [Google Scholar]
  19. Heinzel F. P., Schoenhaut D. S., Rerko R. M., Rosser L. E., Gately M. K. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. doi: 10.1084/jem.177.5.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hirsch F., Couderc J., Sapin C., Fournie G., Druet P. Polyclonal effect of HgCl2 in the rat, its possible role in an experimental autoimmune disease. Eur J Immunol. 1982 Jul;12(7):620–625. doi: 10.1002/eji.1830120716. [DOI] [PubMed] [Google Scholar]
  21. Hu H., Abedi-Valugerdi M., Möller G. Pretreatment of lymphocytes with mercury in vitro induces a response in T cells from genetically determined low-responders and a shift of the interleukin profile. Immunology. 1997 Feb;90(2):198–204. doi: 10.1046/j.1365-2567.1997.00145.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hu H., Möller G., Abedi-Valugerdi M. Thiol compounds inhibit mercury-induced immunological and immunopathological alterations in susceptible mice. Clin Exp Immunol. 1997 Jan;107(1):68–75. doi: 10.1046/j.1365-2249.1997.d01-903.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hultman P., Eneström S., Pollard K. M., Tan E. M. Anti-fibrillarin autoantibodies in mercury-treated mice. Clin Exp Immunol. 1989 Dec;78(3):470–477. [PMC free article] [PubMed] [Google Scholar]
  24. Hultman P., Turley S. J., Eneström S., Lindh U., Pollard K. M. Murine genotype influences the specificity, magnitude and persistence of murine mercury-induced autoimmunity. J Autoimmun. 1996 Apr;9(2):139–149. doi: 10.1006/jaut.1996.0017. [DOI] [PubMed] [Google Scholar]
  25. Jeannin P., Delneste Y., Lecoanet-Henchoz S., Gauchat J. F., Life P., Holmes D., Bonnefoy J. Y. Thiols decrease human interleukin (IL) 4 production and IL-4-induced immunoglobulin synthesis. J Exp Med. 1995 Dec 1;182(6):1785–1792. doi: 10.1084/jem.182.6.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Johansson U., Sander B., Hultman P. Effects of the murine genotype on T cell activation and cytokine production in murine mercury-induced autoimmunity. J Autoimmun. 1997 Aug;10(4):347–355. doi: 10.1006/jaut.1997.0149. [DOI] [PubMed] [Google Scholar]
  27. Kono D. H., Balomenos D., Pearson D. L., Park M. S., Hildebrandt B., Hultman P., Pollard K. M. The prototypic Th2 autoimmunity induced by mercury is dependent on IFN-gamma and not Th1/Th2 imbalance. J Immunol. 1998 Jul 1;161(1):234–240. [PubMed] [Google Scholar]
  28. Kubicka-Muranyi M., Griem P., Lübben B., Rottmann N., Lührmann R., Gleichmann E. Mercuric-chloride-induced autoimmunity in mice involves up-regulated presentation by spleen cells of altered and unaltered nucleolar self antigen. Int Arch Allergy Immunol. 1995 Sep;108(1):1–10. doi: 10.1159/000237110. [DOI] [PubMed] [Google Scholar]
  29. Kubicka-Muranyi M., Kremer J., Rottmann N., Lübben B., Albers R., Bloksma N., Lührmann R., Gleichmann E. Murine systemic autoimmune disease induced by mercuric chloride: T helper cells reacting to self proteins. Int Arch Allergy Immunol. 1996 Jan;109(1):11–20. doi: 10.1159/000237226. [DOI] [PubMed] [Google Scholar]
  30. Magram J., Connaughton S. E., Warrier R. R., Carvajal D. M., Wu C. Y., Ferrante J., Stewart C., Sarmiento U., Faherty D. A., Gately M. K. IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity. 1996 May;4(5):471–481. doi: 10.1016/s1074-7613(00)80413-6. [DOI] [PubMed] [Google Scholar]
  31. Mathieson P. W., Gillespie K. M. Cloning of a partial cDNA for rat interleukin-12 (IL-12) and analysis of IL-12 expression in vivo. Scand J Immunol. 1996 Jul;44(1):11–14. doi: 10.1046/j.1365-3083.1996.d01-279.x. [DOI] [PubMed] [Google Scholar]
  32. Mathieson P. W. Mercuric chloride-induced autoimmunity. Autoimmunity. 1992;13(3):243–247. doi: 10.3109/08916939209004830. [DOI] [PubMed] [Google Scholar]
  33. Meister A., Anderson M. E. Glutathione. Annu Rev Biochem. 1983;52:711–760. doi: 10.1146/annurev.bi.52.070183.003431. [DOI] [PubMed] [Google Scholar]
  34. Monestier M., Losman M. J., Novick K. E., Aris J. P. Molecular analysis of mercury-induced antinucleolar antibodies in H-2S mice. J Immunol. 1994 Jan 15;152(2):667–675. [PubMed] [Google Scholar]
  35. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  36. Ochel M., Vohr H. W., Pfeiffer C., Gleichmann E. IL-4 is required for the IgE and IgG1 increase and IgG1 autoantibody formation in mice treated with mercuric chloride. J Immunol. 1991 May 1;146(9):3006–3011. [PubMed] [Google Scholar]
  37. Oliveira D. B., Gillespie K., Wolfreys K., Mathieson P. W., Qasim F., Coleman J. W. Compounds that induce autoimmunity in the brown Norway rat sensitize mast cells for mediator release and interleukin-4 expression. Eur J Immunol. 1995 Aug;25(8):2259–2264. doi: 10.1002/eji.1830250822. [DOI] [PubMed] [Google Scholar]
  38. Pelletier L., Pasquier R., Guettier C., Vial M. C., Mandet C., Nochy D., Bazin H., Druet P. HgC12 induces T and B cells to proliferate and differentiate in BN rats. Clin Exp Immunol. 1988 Feb;71(2):336–342. [PMC free article] [PubMed] [Google Scholar]
  39. Peterson J. D., Herzenberg L. A., Vasquez K., Waltenbaugh C. Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3071–3076. doi: 10.1073/pnas.95.6.3071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pollard K. M., Lee D. K., Casiano C. A., Bluthner M., Johnston M. M., Tan E. M. The autoimmunity-inducing xenobiotic mercury interacts with the autoantigen fibrillarin and modifies its molecular and antigenic properties. J Immunol. 1997 Apr 1;158(7):3521–3528. [PubMed] [Google Scholar]
  41. Prigent P., Saoudi A., Pannetier C., Graber P., Bonnefoy J. Y., Druet P., Hirsch F. Mercuric chloride, a chemical responsible for T helper cell (Th)2-mediated autoimmunity in brown Norway rats, directly triggers T cells to produce interleukin-4. J Clin Invest. 1995 Sep;96(3):1484–1489. doi: 10.1172/JCI118185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Pusey C. D., Bowman C., Morgan A., Weetman A. P., Hartley B., Lockwood C. M. Kinetics and pathogenicity of autoantibodies induced by mercuric chloride in the brown Norway rat. Clin Exp Immunol. 1990 Jul;81(1):76–82. doi: 10.1111/j.1365-2249.1990.tb05294.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Reardon C. L., Lucas D. O. Heavy-metal mitogenesis: Zn++ and Hg++ induce cellular cytotoxicity and interferon production in murine T lymphocytes. Immunobiology. 1987 Nov;175(5):455–469. doi: 10.1016/S0171-2985(87)80073-6. [DOI] [PubMed] [Google Scholar]
  44. Reuter R., Tessars G., Vohr H. W., Gleichmann E., Lührmann R. Mercuric chloride induces autoantibodies against U3 small nuclear ribonucleoprotein in susceptible mice. Proc Natl Acad Sci U S A. 1989 Jan;86(1):237–241. doi: 10.1073/pnas.86.1.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Robinson C. J., White H. J., Rose N. R. Murine strain differences in response to mercuric chloride: antinucleolar antibodies production does not correlate with renal immune complex deposition. Clin Immunol Immunopathol. 1997 May;83(2):127–138. doi: 10.1006/clin.1997.4336. [DOI] [PubMed] [Google Scholar]
  46. Robinson D., Shibuya K., Mui A., Zonin F., Murphy E., Sana T., Hartley S. B., Menon S., Kastelein R., Bazan F. IGIF does not drive Th1 development but synergizes with IL-12 for interferon-gamma production and activates IRAK and NFkappaB. Immunity. 1997 Oct;7(4):571–581. doi: 10.1016/s1074-7613(00)80378-7. [DOI] [PubMed] [Google Scholar]
  47. Roos A., Claessen N., Schilder-Tol E. J., Chand M. A., Weening J. J., Aten J. Thiol levels in CD134-defined subsets of rat T lymphocytes: possible implications for HgCl2-induced immune dysregulation. Biochem Biophys Res Commun. 1997 Nov 17;240(2):452–457. doi: 10.1006/bbrc.1997.7679. [DOI] [PubMed] [Google Scholar]
  48. Saoudi A., Castedo M., Nochy D., Mandet C., Pasquier R., Druet P., Pelletier L. Self-reactive anti-class II T helper type 2 cell lines derived from gold salt-injected rats trigger B cell polycolonal activation and transfer autoimmunity in CD8-depleted normal syngeneic recipients. Eur J Immunol. 1995 Jul;25(7):1972–1979. doi: 10.1002/eji.1830250726. [DOI] [PubMed] [Google Scholar]
  49. Seder R. A., Paul W. E. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994;12:635–673. doi: 10.1146/annurev.iy.12.040194.003223. [DOI] [PubMed] [Google Scholar]
  50. Sypek J. P., Chung C. L., Mayor S. E., Subramanyam J. M., Goldman S. J., Sieburth D. S., Wolf S. F., Schaub R. G. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993 Jun 1;177(6):1797–1802. doi: 10.1084/jem.177.6.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Takeda K., Tsutsui H., Yoshimoto T., Adachi O., Yoshida N., Kishimoto T., Okamura H., Nakanishi K., Akira S. Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity. 1998 Mar;8(3):383–390. doi: 10.1016/s1074-7613(00)80543-9. [DOI] [PubMed] [Google Scholar]
  52. Trembleau S., Penna G., Bosi E., Mortara A., Gately M. K., Adorini L. Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med. 1995 Feb 1;181(2):817–821. doi: 10.1084/jem.181.2.817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993 Jul;14(7):335–338. doi: 10.1016/0167-5699(93)90230-I. [DOI] [PubMed] [Google Scholar]
  54. Weaver C. T., Hawrylowicz C. M., Unanue E. R. T helper cell subsets require the expression of distinct costimulatory signals by antigen-presenting cells. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8181–8185. doi: 10.1073/pnas.85.21.8181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. van Vliet E., Uhrberg M., Stein C., Gleichmann E. MHC control of IL-4-dependent enhancement of B cell Ia expression and Ig class switching in mice treated with mercuric chloride. Int Arch Allergy Immunol. 1993;101(4):392–401. doi: 10.1159/000236482. [DOI] [PubMed] [Google Scholar]
  56. van der Meide P. H., de Labie M. C., Botman C. A., Aten J., Weening J. J. Nitric oxide suppresses IFN-gamma production in the spleen of mercuric chloride-exposed brown Norway rats. Cell Immunol. 1995 Apr 1;161(2):195–206. doi: 10.1006/cimm.1995.1027. [DOI] [PubMed] [Google Scholar]
  57. van der Meide P. H., de Labie M. C., Botman C. A., van Bennekom W. P., Olsson T., Aten J., Weening J. J. Mercuric chloride down-regulates T cell interferon-gamma production in brown Norway but not in Lewis rats; role of glutathione. Eur J Immunol. 1993 Mar;23(3):675–681. doi: 10.1002/eji.1830230316. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES