Induction of distinct TLR2-mediated proinflammatory and proadhesive signaling pathways in response to Porphyromonas gingivalis fimbriae.
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-kappaB-dependent inflammatory cytokines, whereas the TLR2 proadhesive pathway is characterized by inside-out signaling that transactivates beta(2) 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 pathway. In contrast, another PI3K downstream target, cytohesin-1, was shown to mediate P. gingivalis fimbria-induced activation of beta(2) 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.
Hajishengallis
George
G
Department of Periodontics/Oral Health and Systemic Disease, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Wang
Min
M
Liang
Shuang
S
D001422:Bacterial Adhesion; D002460:Cell Line; D010861:Fimbriae, Bacterial / Q000276:immunology*; D006801:Humans; D007249:Inflammation; D008562:Membrane Glycoproteins / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology*
C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D051195:Toll-Like Receptor 2; D019869:Phosphatidylinositol 3-Kinases