Low-dose mercuric chloride induces resistance in brown norway rats to further mercuric chloride by up-regulation of interferon-γ

Abstract

Mercuric chloride induces autoimmunity in Brown Norway rats with polyclonal B-cell activation, hyper-IgE and multiple autoantibodies. Pre- treatment with low-dose HgCl 2 (one-tenth of the standard dose) induces resistance to later full-dose HgCl 2; we have studied the mechanism of this resistance. Brown Norway rats given low-dose HgCl 2 showed only a modest increase in serum IgE level, three logs lower than rats given standard-dose HgCl 2, and no up-regulation of splenic interleukin (IL)-4 mRNA. There was up-regulation of splenic interferon (IFN)-γ gene expression and a progressive rise in serum IFN-γ. Neither IL-12 nor IL-18 were induced, but there was up-regulation of IL-12 receptor β2-chain (IL-12Rβ2) expression. IL-10 and transforming growth factor (TGF)-β expression did not change. Serum IgE and splenic IL-4 mRNA expression remained static when these rats were rechallenged, confirming resistance. Thereafter IFN-γ expression gradually fell, after which IL-4 expression and serum IgE rose slightly. Our observations suggest that low-dose HgCl 2 confers protection in Brown Norway rats to further HgCl 2 by up-regulation of IFN-γ, associated with enhanced IL-12Rβ2 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.