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25b-CATENIN, BUT NOT NF-kB, MEDIATES PAR-2-INDUCED COX-2 EXPRESSION IN EPITHELIAL CELLS H Wang, MD Hollenberg, WK MacNaughton BACKGROUND: Proteinase-activated receptor-2 (PAR-2) is known to participate in inflammatory processes. Because the activation of PAR-2 can increase the cellular expression of COX-2 and matrix metalloproteinases (MMPs), we propose that PAR-2 may be involved in cancer-related inflammatory responses. We therefore tested the hypothesis that oncogenic
METHODS AND RESULTS: A human lung alveolar cell-derived epithelial cell line, A549, was used in the study since it is an excellent model to study PAR-2-induced COX-2 expression. The selective PAR-2 activating peptide, SLIGRL-NH2, was used to stimulate PAR-2. Treatment of A549 cells with SLIGRL-NH2 dramatically increased the expression of COX-2, as measured by immunostain, Western blot and RT-PCR analysis. Using A549 cells transiently transfected with luciferase reporter constructs for monitoring either b-catenin or NF-kB-regulated transcriptional activity, we found that treatment of cells with SLIGRL-NH2 induced a 5-fold increase in b-catenin (but not NF-kB)-mediated transcriptional activity. Moreover, transfection with a b-catenin-targeted siRNA construct which reduced both the b-catenin protein level and its transcriptional activity, significantly blocked PAR-2-induced COX-2 expression. Pretreatment of cells with inhibitors of either matrix metalloproteinases (MMPs) (BB94) or MAPKinase (PD98059) not only reduced PAR-2-induced transcriptional activation of b-catenin, but also attenuated COX-2 expression.
CONCLUSIONS: PAR-2 activation increased the transcriptional activity of b-catenin through MAPK- and MMP-related pathways, and thereby increased COX-2 expression in A549 epithelial cells. We suggest that PAR-2 plays an important role in cancer-related inflammation via mechanisms involving b-catenin, COX-2 and MMPs.