Role of ASC in the Mouse Model ofHelicobacter pyloriInfection

Abstract

Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) is an adaptor molecule activating caspase-1 that stimulates pro-interleukin-1beta (pro-IL-1beta) and pro-IL-18, two pro-inflammatory cytokines with critical functions in host defense against a variety of pathogens. In this study, we investigated the role of ASC in the host defense against Helicobacter pylori utilizing ASC-deficient mice. Mice were orally inoculated with H. pylori; bacterial load, degree of gastritis, and mucosal levels of inflammatory cytokines were analyzed and compared with those obtained from wild-type mice. We found more prominent H. pylori colonization in ASC-deficient mice, as revealed by colony-forming unit counts. Both groups of mice developed gastritis; however, ASC-deficient mice showed significant attenuation of inflammation despite high H. pylori colonization. ELISA, immunohistochemistry, and quantitative RT-PCR analyses revealed complete suppression of IL-1beta and IL-18, and substantial reduction of interferon-gamma (IFN-gamma) expression, in ASC-deficient mice without apparent upregulation of other cytokines, including IL-10 and tumor necrosis factor-alpha. These results as a whole indicate that ASC exerts considerable influence on the host defense, acting through IL-1beta/IL-18 and subsequent IFN-gamma production, which in turn contributes to continuous chronic inflammatory response and consequent reduction of H. pylori colonization.