1. PAR1- and PAR2-induced innate immune markers are negatively regulated by PI3K/Akt signaling pathway in oral keratinocytes
- Author
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Beverly A. Dale, Dennis H. DiJulio, Jonathan Y. An, Maryam G. Rohani, Beth M. Hacker, and Whasun O. Chung
- Subjects
MAPK/ERK pathway ,Keratinocytes ,lcsh:Immunologic diseases. Allergy ,Chemokine ,Proteases ,Chemokine CXCL5 ,Immunology ,Down-Regulation ,Biology ,p38 Mitogen-Activated Protein Kinases ,03 medical and health sciences ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Humans ,Receptor, PAR-2 ,Receptor, PAR-1 ,Receptor ,Periodontitis ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Mouth ,Innate immune system ,Chemokine CCL20 ,Mitogen-Activated Protein Kinase 3 ,Immunity, Innate ,Cell biology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Signal transduction ,lcsh:RC581-607 ,Chemokines, CXC ,Proto-Oncogene Proteins c-akt ,Research Article ,Signal Transduction - Abstract
Background Protease-Activated Receptors (PARs), members of G-protein-coupled receptors, are activated by proteolytic activity of various proteases. Activation of PAR1 and PAR2 triggers innate immune responses in human oral keratinocytes (HOKs), but the signaling pathways downstream of PAR activation in HOKs have not been clearly defined. In this study, we aimed to determine if PAR1- and PAR2-mediated signaling differs in the induction of innate immune markers CXCL3, CXCL5 and CCL20 via ERK, p38 and PI3K/Akt. Results Our data show the induction of innate immunity by PAR1 requires both p38 and ERK MAP kinases, while PAR2 prominently signals via p38. However, inhibition of PI3K enhances expression of innate immune markers predominantly via suppressing p38 phosphorylation signaled by PAR activation. Conclusion Our data indicate that proteases mediating PAR1 and PAR2 activation differentially signal via MAP kinase cascades. In addition, the production of chemokines induced by PAR1 and PAR2 is suppressed by PI3K/Akt, thus keeping the innate immune responses of HOK in balance. The results of our study provide a novel insight into signaling pathways involved in PAR activation.
- Published
- 2010