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Cutting Edge: ASC Mediates the Induction of Multiple Cytokines by Porphyromonas gingivalis via Caspase-1-Dependent and -Independent Pathways¹

Debra J. Taxman^*, Jinghua Zhang^*, Catherine Champagne, Daniel T. Bergstralh^*, Heather A. Iocca^*, John D. Lich^* and Jenny Pan-Yun Ting^2,*

^* Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, and Department of Periodontology, Center for Oral and Systemic Diseases, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599

Porphyromonas gingivalis (Pg) is a major etiologic agent for chronic periodontitis. Tissue destruction by Pg results partly from induction of host inflammatory responses through TLR2 signaling. This work examines the role of apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), an adaptor molecule important for TLR-mediated caspase-1 activation. Results demonstrate that ASC levels are stable upon infection of human THP1 monocytic cells with Pg but decrease after cytokine induction. Using short hairpin RNA, we demonstrate an essential role for ASC in induction of IL-1 by TLR2, 4, and 5 agonists, live Escherichia coli, and Pg. Induction of IL-6, IL-8, IL-10, and TNF also requires ASC, but this induction is not inhibited by IL-1 receptor antagonist or caspase-1 inhibitor. Similar results in U937 indicate broad applicability of these findings. Pg-infected ASC knockdown THP1 cells exhibit reduced transcript levels and NF-B activation. These results suggest a role for ASC in cytokine induction by Pg involving both caspase-1-dependent and -independent mechanisms.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by National Institutes of Health Grants DK38108, DE16326, AI63031, and AI57175.

² Address correspondence and reprint requests to Dr. Jenny Pan-Yun Ting, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599. E-mail address: panyun{at}med.unc.edu

³ Abbreviations used in this paper: Pg, Porphyromonas gingivalis; ASC, apoptosis-associated speck-like protein containing a caspase-recruitment domain; shRNA, short hairpin RNA.

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