Signal Transduction Pathways Involved in the Synergistic Stimulation of Prostaglandin Production by Interleukin-1β and Tumor Necrosis Factor a in Human Gingival Fibroblasts

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Abstract
Accumulating evidence indicates that prostaglandins play an important role in the pathogenesis of periodontal disease. In this study, the effects and interactions between IL-1β and TNFa on prostaglandin production and its regulation were investigated. The cytokines IL-1β and TNFa stimulated prostaglandin E2 (PGE2) and prostacyclin (PGI2) production in gingival fibroblasts. Simultaneous treatment of the cells with IL-1β and TNFa resulted in a synergistic stimulation of PGE2 and PGI2 formation. IL-1β and, to a lesser extent, TNFa stimulated the release of 3H-arachidonic acid (3H-AA), and simultaneous addition of IL-1β and TNFa further increased the release of 3H-AA from pre-labeled gingival fibroblasts. Furthermore, IL-1β and, to a lesser extent, TNFa induced the expression of cyclooxygenase-2 (COX-2) mRNA. Simultaneous addition of IL-1β and TNFa synergistically enhanced COX-2 mRNA levels, accompanied by a corresponding stimulation of PGE2 synthesis. Neither IL-1β, TNFa, nor the combination of these two cytokines affected COX-1 mRNA levels. PMA, known to activate protein kinase C (PKC), enhanced the stimulatory effect of IL-1β, TNFa, and the combination on COX-2 mRNA levels accompanied by a corresponding increase in PGE2 production. The phospholipase A2 (PLA2) inhibitor, BPB, and the PKC inhibitor, BIS, reduced PGE2 production, whereas dexamethasone, indomethacin, and NS-398 completely abolished PGE2 production induced by IL-1β, TNFa, and the combination. The study indicates that the synergistic stimulation of prostaglandin production by IL-1β, and TNFa is mediated partly at the level of COX-2 and partly at the level of PLA2 and that PKC is involved in the signal transduction of the synergy between the two cytokines. The synergy between IL-1β and TNFa may play an important role in the inflammatory processes in gingival tissue in vivo.

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