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. 1995 Sep;96(3):1484–1489. doi: 10.1172/JCI118185

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.

P Prigent 1, A Saoudi 1, C Pannetier 1, P Graber 1, J Y Bonnefoy 1, P Druet 1, F Hirsch 1
PMCID: PMC185772  PMID: 7657819

Abstract

Mercurials may induce immune manifestations in susceptible individuals. Mercuric chloride (HgCl2) induced autoimmunity in the Brown Norway (BN) strain but an immuno-suppression in the Lewis strain with, however, autoreactive anti-class II T cells present in both strains. In the present study we looked at modifications of cytokine production by PCR and cytofluorometric analyses in normal BN and Lewis rat splenocytes, cultured with or without HgCl2. Unfractionated BN rat splenocytes and purified T cells exposed to HgCl2 expressed high levels of IL-4 mRNA. Increase in class II and CD23 molecule expression on B cells was partly inhibited by anti-IL-4 mAb showing that IL-4 was produced. By contrast, no overexpression of IL-4 mRNA could be seen in Lewis rats. Although an increase in class II molecule expression was observed suggesting that other T helper cell 2 cytokines were produced, there was also a concomitant decrease in CD23 molecule expression that was abrogated after addition of an anti-IFN-gamma mAb to the culture. IFN-gamma mRNA production was induced in unfractionated spleen cells and T cells from both strains after HgCl2 exposure. Altogether these findings demonstrate that HgCl2 has very early direct effects on cytokine production and that these effects differ depending on the strain. The early effect on IL-4 production observed on BN rat spleen cells and T cells may explain that the autoreactive anti-class II T cells that are found in HgCl2-injected BN rats have a Th2 phenotype.

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Selected References

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  1. Adler R., Boxstein D., Schaff P., Kelly D. Metallic mercury vapor poisoning simulating mucocutaneous lymph node syndrome. J Pediatr. 1982 Dec;101(6):967–968. doi: 10.1016/s0022-3476(82)80023-1. [DOI] [PubMed] [Google Scholar]
  2. Bendelac A., Matzinger P., Seder R. A., Paul W. E., Schwartz R. H. Activation events during thymic selection. J Exp Med. 1992 Mar 1;175(3):731–742. doi: 10.1084/jem.175.3.731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Castedo M., Pelletier L., Rossert J., Pasquier R., Villarroya H., Druet P. Mercury-induced autoreactive anti-class II T cell line protects from experimental autoimmune encephalomyelitis by the bias of CD8+ antiergotypic cells in Lewis rats. J Exp Med. 1993 Apr 1;177(4):881–889. doi: 10.1084/jem.177.4.881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chan S. H., Kobayashi M., Santoli D., Perussia B., Trinchieri G. Mechanisms of IFN-gamma induction by natural killer cell stimulatory factor (NKSF/IL-12). Role of transcription and mRNA stability in the synergistic interaction between NKSF and IL-2. J Immunol. 1992 Jan 1;148(1):92–98. [PubMed] [Google Scholar]
  5. 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]
  6. Cuturi M. C., Josien R., Douillard P., Pannetier C., Cantarovich D., Smit H., Ménoret S., Pouletty P., Clayberger C., Soulillou J. P. Prolongation of allogeneic heart graft survival in rats by administration of a peptide (a.a. 75-84) from the alpha 1 helix of the first domain of HLA-B7 01. Transplantation. 1995 Mar 15;59(5):661–669. doi: 10.1097/00007890-199503150-00003. [DOI] [PubMed] [Google Scholar]
  7. Delespesse G., Suter U., Mossalayi D., Bettler B., Sarfati M., Hofstetter H., Kilcherr E., Debre P., Dalloul A. Expression, structure, and function of the CD23 antigen. Adv Immunol. 1991;49:149–191. doi: 10.1016/s0065-2776(08)60776-2. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Dokter W. H., Esselink M. T., Sierdsema S. J., Halie M. R., Vellenga E. Transcriptional and posttranscriptional regulation of the interleukin-4 and interleukin-3 genes in human T cells. Blood. 1993 Jan 1;81(1):35–40. [PubMed] [Google Scholar]
  10. Druet E., Sapin C., Günther E., Feingold N., Druet P. Mercuric chloride-induced anti-glomerular basement membrane antibodies in the rat: genetic control. Eur J Immunol. 1977 Jun;7(6):348–351. doi: 10.1002/eji.1830070605. [DOI] [PubMed] [Google Scholar]
  11. Druet P., Druet E., Potdevin F., Sapin C. Immune type glomerulonephritis induced by HgCl2 in the Brown Norway rat. Ann Immunol (Paris) 1978 Oct-Dec;129 100(6):777–792. [PubMed] [Google Scholar]
  12. Dubey C., Bellon B., Hirsch F., Kuhn J., Vial M. C., Goldman M., Druet P. Increased expression of class II major histocompatibility complex molecules on B cells in rats susceptible or resistant to HgCl2-induced autoimmunity. Clin Exp Immunol. 1991 Oct;86(1):118–123. doi: 10.1111/j.1365-2249.1991.tb05783.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Flores-Romo L., Shields J., Humbert Y., Graber P., Aubry J. P., Gauchat J. F., Ayala G., Allet B., Chavez M., Bazin H. Inhibition of an in vivo antigen-specific IgE response by antibodies to CD23. Science. 1993 Aug 20;261(5124):1038–1041. doi: 10.1126/science.8351517. [DOI] [PubMed] [Google Scholar]
  14. Gillespie K. M., Qasim F. J., Tibbatts L. M., Thiru S., Oliveira D. B., Mathieson P. W. Interleukin-4 gene expression in mercury-induced autoimmunity. Scand J Immunol. 1995 Mar;41(3):268–272. doi: 10.1111/j.1365-3083.1995.tb03563.x. [DOI] [PubMed] [Google Scholar]
  15. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  16. Go N. F., Castle B. E., Barrett R., Kastelein R., Dang W., Mosmann T. R., Moore K. W., Howard M. Interleukin 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells. J Exp Med. 1990 Dec 1;172(6):1625–1631. doi: 10.1084/jem.172.6.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. Holst M., Nordlind K. Phosphorylation of nuclear proteins of peripheral blood T lymphocytes activated by nickel sulfate and mercuric chloride. Int Arch Allergy Appl Immunol. 1988;85(3):337–340. doi: 10.1159/000234528. [DOI] [PubMed] [Google Scholar]
  20. Kimata H., Shinomiya K., Mikawa H. Selective enhancement of human IgE production in vitro by synergy of pokeweed mitogen and mercuric chloride. Clin Exp Immunol. 1983 Jul;53(1):183–191. [PMC free article] [PubMed] [Google Scholar]
  21. Kusakawa S., Heiner D. C. Elevated levels of immunoglobulin E in the acute febrile mucocutaneous lymph node syndrome. Pediatr Res. 1976 Feb;10(2):108–111. doi: 10.1203/00006450-197602000-00007. [DOI] [PubMed] [Google Scholar]
  22. Manetti R., Parronchi P., Giudizi M. G., Piccinni M. P., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mathieson P. W., Thiru S., Oliveira D. B. Mercuric chloride-treated brown Norway rats develop widespread tissue injury including necrotizing vasculitis. Lab Invest. 1992 Jul;67(1):121–129. [PubMed] [Google Scholar]
  24. Mathieson P. W., Thiru S., Oliveira D. B. Regulatory role of OX22high T cells in mercury-induced autoimmunity in the brown Norway rat. J Exp Med. 1993 May 1;177(5):1309–1316. doi: 10.1084/jem.177.5.1309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McKnight A. J., Barclay A. N., Mason D. W. Molecular cloning of rat interleukin 4 cDNA and analysis of the cytokine repertoire of subsets of CD4+ T cells. Eur J Immunol. 1991 May;21(5):1187–1194. doi: 10.1002/eji.1830210514. [DOI] [PubMed] [Google Scholar]
  26. McKnight A. J., Classon B. J. Biochemical and immunological properties of rat recombinant interleukin-2 and interleukin-4. Immunology. 1992 Feb;75(2):286–292. [PMC free article] [PubMed] [Google Scholar]
  27. Nakayama H., Niki F., Shono M., Hada S. Mercury exanthem. Contact Dermatitis. 1983 Sep;9(5):411–417. doi: 10.1111/j.1600-0536.1983.tb04439.x. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Pannetier C., Delassus S., Darche S., Saucier C., Kourilsky P. Quantitative titration of nucleic acids by enzymatic amplification reactions run to saturation. Nucleic Acids Res. 1993 Feb 11;21(3):577–583. doi: 10.1093/nar/21.3.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Paul W. E., Seder R. A., Plaut M. Lymphokine and cytokine production by Fc epsilon RI+ cells. Adv Immunol. 1993;53:1–29. [PubMed] [Google Scholar]
  31. 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]
  32. Pelletier L., Pasquier R., Rossert J., Druet P. HgCl2 induces nonspecific immunosuppression in Lewis rats. Eur J Immunol. 1987 Jan;17(1):49–54. doi: 10.1002/eji.1830170109. [DOI] [PubMed] [Google Scholar]
  33. Pelletier L., Pasquier R., Rossert J., Vial M. C., Mandet C., Druet P. Autoreactive T cells in mercury-induced autoimmunity. Ability to induce the autoimmune disease. J Immunol. 1988 Feb 1;140(3):750–754. [PubMed] [Google Scholar]
  34. Prouvost-Danon A., Abadie A., Sapin C., Bazin H., Druet P. Induction of IgE synthesis and potentiation of anti-ovalbumin IgE antibody response by HgCl2 in the rat. J Immunol. 1981 Feb;126(2):699–792. [PubMed] [Google Scholar]
  35. Punnonen J., Aversa G., Cocks B. G., McKenzie A. N., Menon S., Zurawski G., de Waal Malefyt R., de Vries J. E. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3730–3734. doi: 10.1073/pnas.90.8.3730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Saoudi A., Kuhn J., Huygen K., de Kozak Y., Velu T., Goldman M., Druet P., Bellon B. TH2 activated cells prevent experimental autoimmune uveoretinitis, a TH1-dependent autoimmune disease. Eur J Immunol. 1993 Dec;23(12):3096–3103. doi: 10.1002/eji.1830231208. [DOI] [PubMed] [Google Scholar]
  38. Scott P. IFN-gamma modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J Immunol. 1991 Nov 1;147(9):3149–3155. [PubMed] [Google Scholar]
  39. Swain S. L., Weinberg A. D., English M., Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990 Dec 1;145(11):3796–3806. [PubMed] [Google Scholar]
  40. Tanaka T., Hu-Li J., Seder R. A., Fazekas de St Groth B., Paul W. E. Interleukin 4 suppresses interleukin 2 and interferon gamma production by naive T cells stimulated by accessory cell-dependent receptor engagement. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5914–5918. doi: 10.1073/pnas.90.13.5914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Todd M. D., Grusby M. J., Lederer J. A., Lacy E., Lichtman A. H., Glimcher L. H. Transcription of the interleukin 4 gene is regulated by multiple promoter elements. J Exp Med. 1993 Jun 1;177(6):1663–1674. doi: 10.1084/jem.177.6.1663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Van Mechelen M., De Wit D., Ryelandt M., Hjulström S., Heynderickx M., Bazin H., Urbain J., Leo O. Induction of Th2 responses to soluble proteins is independent of B cell tolerance status. Int Immunol. 1995 Feb;7(2):199–205. doi: 10.1093/intimm/7.2.199. [DOI] [PubMed] [Google Scholar]
  43. Yoshimoto T., Paul W. E. CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3. J Exp Med. 1994 Apr 1;179(4):1285–1295. doi: 10.1084/jem.179.4.1285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. 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]
  45. van der Meide P. H., Borman A. H., Beljaars H. G., Dubbeld M. A., Botman C. A., Schellekens H. Isolation and characterization of monoclonal antibodies directed to rat interferon-gamma. Lymphokine Res. 1989 Winter;8(4):439–449. [PubMed] [Google Scholar]
  46. 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]
  47. 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]

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