Low-dose mercuric chloride induces resistance in brown norway rats to further mercuric chloride by up-regulation of interferon-gamma.
Mercuric chloride induces autoimmunity in Brown Norway rats with polyclonal B-cell activation, hyper-IgE and multiple autoantibodies. Pre-treatment with low-dose HgCl2 (one-tenth of the standard dose) induces resistance to later full-dose HgCl2; we have studied the mechanism of this resistance. Brown Norway rats given low-dose HgCl2 showed only a modest increase in serum IgE level, three logs lower than rats given standard-dose HgCl2, and no up-regulation of splenic interleukin (IL)-4 mRNA. There was up-regulation of splenic interferon (IFN)-gamma gene expression and a progressive rise in serum IFN-gamma. Neither IL-12 nor IL-18 were induced, but there was up-regulation of IL-12 receptor beta2-chain (IL-12Rbeta2) expression. IL-10 and transforming growth factor (TGF)-beta expression did not change. Serum IgE and splenic IL-4 mRNA expression remained static when these rats were rechallenged, confirming resistance. Thereafter IFN-gamma expression gradually fell, after which IL-4 expression and serum IgE rose slightly. Our observations suggest that low-dose HgCl2 confers protection in Brown Norway rats to further HgCl2 by up-regulation of IFN-gamma, associated with enhanced IL-12Rbeta2 expression. The immunological response to HgCl2 in susceptible rat strains is more complex than previously appreciated and is dose dependent, with low doses inducing a T helper '(Th)1' type of response in contrast to the 'Th2' type response associated with standard doses.
Szeto
C
C
Academic Renal Unit, University of Bristol, Bristol, UK.
Gillespie
K M
KM
Mathieson
P W
PW
D000818:Animals; D016207:Cytokines / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000276:immunology; D015870:Gene Expression; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics / Q000276:immunology*; D008297:Male; D008627:Mercuric Chloride / Q000276:immunology*; D016133:Polymerase Chain Reaction / Q000379:methods; D051381:Rats; D011914:Rats, Inbred BN; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation
D016207:Cytokines; D008627:Mercuric Chloride; D007371:Interferon-gamma