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The Proinflammatory Cytokine Response to Chlamydia trachomatis Elementary Bodies in Human Macrophages Is Partly Mediated by a Lipoprotein, the Macrophage Infectivity Potentiator, through TLR2/TLR1/TLR6 and CD14¹

Sylvette Bas^2,*, Laurence Neff^*,, Madeleine Vuillet^*, Ursula Spenato^*, Tsukasa Seya, Misako Matsumoto and Cem Gabay^*,

^* Division of Rheumatology, Department of Internal Medicine, University Hospital, and Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland; and Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Chlamydiae components and signaling pathway(s) responsible for the production of proinflammatory cytokines by human monocytes/macrophages are not clearly identified. To this aim, Chlamydia trachomatis-inactivated elementary bodies (EB) as well as the following seven individual Ags were tested for their ability to induce the production of proinflammatory cytokines by human monocytes/macrophages and THP-1 cells: purified LPS, recombinant heat shock protein (rhsp)70, rhsp60, rhsp10, recombinant polypeptide encoded by open reading frame 3 of the plasmid (rpgp3), recombinant macrophage infectivity potentiator (rMip), and recombinant outer membrane protein 2 (rOmp2). Aside from EB, rMip displayed the highest ability to induce release of IL-1β, TNF-, IL-6, and IL-8. rMip proinflammatory activity could not be attributed to Escherichia coli LPS contamination as determined by the Limulus Amoebocyte lysate assay, insensitivity to polymyxin B (50 µg/ml), and different serum requirement. We have recently demonstrated that Mip is a "classical" bacterial lipoprotein, exposed at the surface of EB. The proinflammatory activity of EB was significantly attenuated in the presence of polyclonal Ab to rMip. Native Mip was able to induce TNF- and IL-8 secretion, whereas a nonlipidated C20A rMip variant was not. Proinflammatory activity of rMip was unaffected by heat or proteinase K treatments but was greatly reduced by treatment with lipases, supporting a role of lipid modification in this process. Stimulating pathways appeared to involve TLR2/TLR1/TLR6 with the help of CD14 but not TLR4. These data support a role of Mip lipoprotein in pathogenesis of C. trachomatis-induced inflammatory responses.

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 was supported by grants from Novartis, Albert-Boeni, and de Reuter Foundations, and from Geneva Academic Society. This work was also supported by Grants 3200B0-107883 (to S.B.) and 3200-107592/1 (to C.G.) from the Swiss National Science Foundation.

² Address correspondence and reprint requests to Dr. Sylvette Bas, Division of Rheumatology, Department of Internal Medicine, University Hospital, 1211 Geneva 14, Switzerland. E-mail address: sylvette.bas{at}hcuge.ch

³ Abbreviations used in this paper: EB, elementary body; hsp, heat shock protein; pgp3, polypeptide encoded by open reading frame 3 of the plasmid; Mip, macrophage infectivity potentiator; Omp2, outer membrane protein 2; WT, wild type; HEK, human embryonic kidney.

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