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J. Biol. Chem., Vol. 282, Issue 38, 27647-27658, September 21, 2007

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Vibrio vulnificus IlpA-induced Cytokine Production Is Mediated by Toll-like Receptor 2^*

Sung Young Goo, Yang Soo Han, Woo Hyang Kim, Kyu-Ho Lee, and Soon-Jung Park¹

From the Department of Environmental Medical Biology and Institute of Tropical Medicine, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 120-752 and the Department of Environmental Science, Hankuk University of Foreign Studies, Yongin 449-791, Republic of Korea

Vibrio vulnificus is a pathogenic bacterium causing primary septicemia, which follows a classical septic shock pathway, including an overwhelming inflammatory cytokine response. In this study, we identified a putative lipoprotein of V. vulnificus, encoded by the ilpA gene, as one of the surface proteins that specifically reacted with the antibodies raised against outer membrane proteins of V. vulnificus. Using a mutant V. vulnificus in which its ilpA gene was knocked out, we found that IlpA is important in the production of interferon- in human peripheral blood mononuclear cells. Production of tumor necrosis factor- and interleukin-6 is also induced by the recombinant IlpA (rIlpA) in human monocytes. Lipidation of the rIlpA was observed by in vivo labeling in Escherichia coli. Experiments using the mutant IlpA, which is unable to be modified by lipidation, indicate that the lipid moiety of this protein has an essential property for cytokine production in human cells. Pretreatment of monocytes with antibodies against Toll-like receptor 2 (TLR2) inhibited production of both tumor necrosis factor- and interleukin-6. The role of TLR2 in IlpA-induced cytokine production was confirmed by an in vitro assay, in which only the TLR2-expressing cells showed a dramatic induction of nuclear factor-B activity by rIlpA. In addition, rIlpA treatment resulted in induction of TLR2 transcription in human cells. In comparison with the wild type V. vulnificus, the ilpA mutant showed a reduced mortality in mice. These results demonstrate that IlpA of V. vulnificus functions as an immunostimulant to human cells via TLR2.

Received for publication, March 5, 2007 , and in revised form, July 19, 2007.

^* This work was supported by the 21st Century Frontier Microbial Genomics and Application Center Program, Ministry of Science and Technology Grant MG05-0201-5-0 (to S.-J. P. and K.-H. L.), Republic of Korea, and in part by Seoul Research and Business Development Program Grant 10580 (to S.-J. P. and K.-H. L.). 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ177330.

¹ To whom correspondence should be addressed. Tel.: 82-2-22281843; Fax: 82-2-3638676; E-mail: sjpark615{at}yuhs.ac.kr.

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