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J. Biol. Chem., Vol. 278, Issue 47, 46252-46260, November 21, 2003

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The Lip Lipoprotein from Neisseria gonorrhoeae Stimulates Cytokine Release and NF-B Activation in Epithelial Cells in a Toll-like Receptor 2-dependent Manner^*

Philip L. Fisette, Sanjay Ram, Jorunn M. Andersen, Wen Guo¶, and Robin R. Ingalls||

From the Division of Infectious Diseases and the ^¶Obesity Research Unit, Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118 and the Norwegian University of Science and Technology, Trondheim 7489, Norway

The human pathogen Neisseria gonorrhoeae produces an array of diseases ranging from urethritis to disseminated gonococcal infections. Early events in the establishment of infection involve interactions between N. gonorrhoeae and the mucosal epithelium, which leads to the local release of inflammatory mediators. Because of this, it is important to identify the bacterial virulence factors and host cell components that contribute to inflammation. Using a series of column chromatography steps, we purified a lipoprotein from N. gonorrhoeae strain F62 called Lip. This outer membrane antigen expresses a conserved epitope known as H.8, which is common to all pathogenic Neisseria species. We found the purified preparation of Lip to be a potent inflammatory mediator capable of inducing the release of the chemokine interleukin (IL)-8 and the cytokine IL-6 by immortalized human endocervical epithelial cells and the production of IL-8 and the activation of the transcription factor NF-B by human embryonic kidney 293 (HEK) cells transfected with toll-like receptor (TLR) 2. Upon removal of Lip by immunoprecipitation, the ability of the H.8/Lip preparation to stimulate NF-B activation was abolished. In addition to TLR2, the activation of NF-B by H.8/Lip in HEK cells was enhanced upon coexpression of TLR1 but not TLR6. These observations provide evidence that Lip is capable of inducing the release of inflammatory mediators from epithelial cells in a TLR2-dependent manner.

Received for publication, June 20, 2003 , and in revised form, September 5, 2003.

^* This work was supported by National Institutes of Health Grants AI46613 (to R. R. I. and J. M. A.), AI38515 (to R. R. I.), AI32725 (to S. R.), T32 HL07501 and T32 AI52070 (to P. L. F.), and DK59261 (to W. G.). 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.

^|| To whom correspondence should be addressed: Boston University School of Medicine, Div. of Infectious Diseases, EBRC Bldg., Rm. 615, 650 Albany St., Boston, MA 02118. Tel.: 617-414-4778; Fax: 617-414-5280; E-mail: ringalls{at}bu.edu.

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