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Role of ASC in the Mouse Model of Helicobacter pylori Infection

Bekale N. Benoit, Motohiro Kobayashi, Masatomo Kawakubo, Michiko Takeoka, Kenji Sano, Jian Zou, Naoki Itano, Hiroko Tsutsui, Tetsuo Noda, Minoru Fukuda, Jun Nakayama and Shun'ichiro Taniguchi

Department of Molecular Oncology, Institute on Aging and Adaptation (BNB,JZ,MT,NI,ST) and Department of Molecular Pathology (MKobayashi,JN), Shinshu University Graduate School of Medicine, Matsumoto, Japan; Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan (MKawakubo,KS); Department of Microbiology, Hyogo College of Medicine, Nishinomiya, Japan (HT); Department of Cellular Biology, Institute of Cancer, Japanese Foundation for Cancer Research, Tokyo, Japan (TN); and Tumor Microenvironment Program, Cancer Research Center, Burnham Institute for Medical Research, La Jolla, California (MF)

Correspondence to: Shun'ichiro Taniguchi, Department of Molecular Oncology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. E-mail: stangch{at}shinshu-u.ac.jp

Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) is an adaptor molecule activating caspase-1 that stimulates pro-interleukin-1β (pro-IL-1β) 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-1β and IL-18, and substantial reduction of interferon- (IFN-) expression, in ASC-deficient mice without apparent upregulation of other cytokines, including IL-10 and tumor necrosis factor-. These results as a whole indicate that ASC exerts considerable influence on the host defense, acting through IL-1β/IL-18 and subsequent IFN- production, which in turn contributes to continuous chronic inflammatory response and consequent reduction of H. pylori colonization. (J Histochem Cytochem 57:327–338, 2009)

Key Words: apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain • IL-1β • IL-18 • INF- • Helicobacter pylori • gastritis

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