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 wi th low-dose HgCl2 (one-tenth of the standard dose) induces resistance to la ter full-dose HgCl2; we have studied the mechanism of this resistance. Brow n Norway rats given low-dose HgCl2 showed only a modest increase in serum I gE level, three logs lower than rats given standard-dose HgCl2, and no up-r egulation of splenic interleukin (IL)-4 mRNA, There was up-regulation of sp lenic interferon (IFN)-gamma gene expression and a progressive rise in seru m IFN-gamma. Neither IL-12 nor IL-18 were induced, but there was up-regulat ion of IL-12 receptor beta 2-chain (IL-12R beta 2) expression. IL-10 and tr ansforming growth factor (TGF)-beta expression did not change. Serum IgE an d splenic IL-4 mRNA expression remained static when these rats were rechall enged, confirming resistance. Thereafter IFN-gamma expression gradually fel l, after which IL-4 expression and serum IgE rose slightly. Our observation s suggest that low-dose HgCl2 confers protection in Brown Norway rats to fu rther HgCl2 by up-regulation of IFN-gamma, associated with enhanced IL-12R beta 2 expression. The immunological response to HgCl2 in susceptible rat s trains is more complex than previously appreciated and is dose dependent, w ith low doses inducing a T helper '(Th)1' type of response in contrast to t he 'Th2' type response associated with standard doses.