Res
Res. cytokines IL-1, TNF-, and IFN-, hypergammaglobulinemia, splenomegaly, CD4+ T-cell activation, and production of autoantibodies. Inflammation in B10.S mice was associated with a selective increase in activity of cysteine cathepsin B but not cathepsins L or S. Increased cathepsin B activity was not dependent on cytokines required for mHgIA but treatment with CA-074, a cathepsin B inhibitor, led to transient reduction of local induration, expression of inflammatory cytokines, and subsequent attenuation of the systemic adaptive immune response. These findings demonstrate that sensitivity to mHgIA (S)-(-)-Perillyl alcohol is linked to an early cathepsin B regulated inflammatory response which can be pharmacologically exploited to abrogate the subsequent adaptive autoimmune response which leads to disease. Keywords: autoimmunity, inflammation, mercuric chloride, cytokines, T-cell activation, cathepsin B. Human exposure to mercury is an environmental trigger in the induction of autoimmunity including production of autoantibodies and proinflammatory cytokines such as IL-1, TNF-, and IFN- and membranous nephropathy (Pollard, 2012). Animal model studies of murine mercury-induced autoimmunity (mHgIA) have contributed significantly to our understanding of the systemic autoimmunity induced by this environmental agent (Germolec locus at the distal end of chromosome 1 (Kono values less than 0.05 were considered significant. RESULTS mHgIA-Resistant DBA/2 Mice Lack Evidence of Induration at the Site of HgCl2 Exposure Mercury exposure induces an inflammatory response, particularly at the site of exposure (Pollard values compare HgCl2-treated mice compared with PBS controls; *(Kono (Maekawa et al., 1998); IL-4, IgE, and IgG1 responses were suppressed and IFN- and IgG2a increased. This may explain why CA-074 was not able to reduce the expression of IFN- and IgG2a antibodies to control levels, although, these levels were significantly lower than in mice exposed to mercury alone. More importantly, the presence of a Th1 response in CA-074-treated mice may explain the development of proinflammatory cytokine expression with longer treatment as induction of mHgIA is dependent upon IFN-. Absence of IFN- suppresses hypergammaglobulinemia, autoantibodies, and immune Mouse monoclonal to NKX3A complex deposition but not T-cell activation (Pollard et al., 2012). It is possible that the suppression of inflammatory factors by CA-074 during the first 7 days involves events that are not IFN- dependent as absence of IFN- did not affect HgCl2-induced increase in cathepsin B activity. Similar observations were made with IL-6- and caspase 1-deficient mice suggesting (S)-(-)-Perillyl alcohol that the effects of these proinflammatory mediators on mHgIA are downstream of the regulation of cathepsin B activity. In conclusion, we report that resistance to mHgIA in DBA/2J mice is associated with the absence of a local inflammatory response at the site of HgCl2 exposure. Attempts to model such resistance using CA-074, a cathepsin B inhibitor, in mHgIA-sensitive mice delayed the inflammatory response and dampened the severity of mHgIA. The data demonstrate that development of mHgIA is coupled to an inflammatory response the magnitude of which is influenced by cathepsin B. FUNDING The National Institute of Environmental Health Sciences (grant numbers Sera007511;, Sera021464;, and Sera022625 to K.M.P.); An NIEHS Product to Support High School and Undergraduate Study Experiences [give quantity Sera007511-S1 to C.B.T], and a Amylin Pharmaceuticals Study Scholarship, and a Julia Brown Research Scholarship to C.B.T. while an undergraduate in the University or college of California at San Diego. ACKNOWLEDGMENTS The authors acknowledge the excellent technical services of the Histology Core Laboratory of The Scripps Study Institute. They say thanks to Dwight H. Kono for his feedback on the article. This is publication quantity 20976 from your Scripps Study Institute. Referrals Abedi-Valugerdi M., Nilsson C., Zargari A., Gharibdoost F., DePierre J. W., Hassan M. (2005). Bacterial lipopolysaccharide both renders resistant mice susceptible to mercury-induced autoimmunity and exacerbates (S)-(-)-Perillyl alcohol such autoimmunity in vulnerable mice. Clin. Exp. Immunol. 141, 238C247. [PMC free article] [PubMed].