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Induction of Distinct TLR2-Mediated Proinflammatory and Proadhesive Signaling Pathways in Response to Porphyromonas gingivalis Fimbriae¹

George Hajishengallis^2,*,, Min Wang^* and Shuang Liang^*

^* Department of Periodontics/Oral Health and Systemic Disease and Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, KY 40292

The oral pathogen Porphyromonas gingivalis, as well as its purified fimbriae, are known to activate TLR2 and induce proinflammatory and proadhesive effects. The TLR2 proinflammatory pathway induces NF-B-dependent inflammatory cytokines, whereas the TLR2 proadhesive pathway is characterized by inside-out signaling that transactivates β₂ integrin adhesive activities. In this article, using dominant-negative or pharmacological approaches, we show that the two pathways bifurcate and proceed independently downstream of TLR2. Whereas the proinflammatory pathway is dependent on the adaptor molecules Toll/IL-1 receptor domain-containing adaptor protein (also known as Mal) and MyD88, the proadhesive pathway is Toll/IL-1 receptor domain-containing adaptor protein/MyD88-independent and proceeds through PI3K-mediated signaling. Although the Ser/Thr kinase Akt is a major downstream target of PI3K and was activated by P. gingivalis fimbriae in a TLR2- and PI3K-dependent way, Akt was shown not to play a role in the proadhesive patway. In contrast, another PI3K downstream target, cytohesin-1, was shown to mediate P. gingivalis fimbria-induced activation of β₂ integrin for ICAM-1 binding. Therefore, P. gingivalis fimbriae activate two distinct TLR2 pathways mediating proinflammatory or proadhesive effects. The delineation of these signaling pathways may provide appropriate targets for selectively inhibiting or enhancing specific activities, depending on whether they undermine or promote the host defense.

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 U.S. Public Health Service Grants DE015254 and DE018292 from the National Institutes of Health/NIDCR (to G.H.).

² Address correspondence and reprint requests to Dr. George Hajishengallis, University of Louisville Health Sciences Center, 501 South Preston Street, Room 206, Louisville, KY 40292. E-mail address: g0haji01{at}louisville.edu

³ Abbreviations used in this paper: TIR, Toll/IL-1 receptor; TIRAP, Toll/IL-1 receptor domain-containing adaptor protein; CR3, complement receptor-3; WT, wild type; PIP3, phosphatidylinositol-(3,4,5)-trisphosphate; MyD88-DN, dominant-negative signaling mutant of human MyD88; TRAM, TRIF-related adaptor molecule; Akt-DN, dominant negative inhibitor of Akt signaling.