Tumor necrosis factor-α inversely regulates prostaglandin D2 and prostaglandin E2 production in murine macrophages -: Synergistic action of cyclic amp on cyclooxygenase-2 expression and prostaglandin E2 synthesis

Increased synthesis of insulin-like growth factor-1 is induced in murine macrophages by prostaglandin E-2 (PGE(2),) and tumor necrosis factor-alpha (TNF alpha). Accordingly, we have investigated mechanisms regulating synthesis of PGE(2), that might contribute to autocrine/paracrine effects on insulin-like growth factor-1 production. In response to zymosan, TNF alpha specifically induced a 5-fold increase in PGE(2), synthesis, at the same time decreasing PGD(2), production in a reciprocal fashion. Activators of cyclic AMP-dependent protein kinase (PKA), such as PGE(2), itself or dibutyryl cyclic AMP, did not modify PGE(2), production by themselves but potentiated the TNF alpha-induced increase in PGE(2),; this effect required both RNA and protein synthesis, No significant change in arachidonate release or production of other eicosanoids was observed. The inducible form of cyclooxygenase-a (COX2) but not of the constitutive form COX1 was implicated in the generation of both PGE(2), and PGD(2), in these cells by use of specific inhibitors and effects of dexamethasone. Neither COX1 nor COX2 protein levels were affected by TNF alpha or PKA activators used alone, whereas in association, marked up-regulation of COX2 mRNA and protein was observed. Incubations of cells carried out with PGH(2), demonstrated that PGE(2), synthase activity was increased after a TNF alpha pretreatment. Taken together, our results suggest that TNF alpha induced a switch from the PGD(2), to PGE(2), synthesis pathway by regulating PGE(2), synthase expression and/or activity and that activators of PKA markedly potentiated the TNF alpha-induced increase in PGE(2), through up-regulation of COX2 gene expression.