INTERFERON-γ AND INTERLEUKIN 4 INHIBIT INTERLEUKIN 1β-INDUCED DELAYED PROSTAGLANDIN E2GENERATION THROUGH SUPPRESSION OF CYCLOOXYGENASE-2 EXPRESSION IN HUMAN FIBROBLASTS

Abstract

Interleukin (IL-)1 stimulates prostaglandin E2(PGE2) generation in fibroblasts, and preferential couplings between particular phospholipase A2(PLA2) and cyclooxygenase (COX) isozymes are implicated with IL-1-induced delayed PGE2generation. The regulatory effects of interferon (IFN)-γ and IL-4 on IL-1β-induced COX, PLA2isoforms expression and terminal delayed PGE2generation were examined in three types of human fibroblasts. These human fibroblasts constitutively expressed cytosolic PLA2(cPLA2) and COX-1 enzymes, and exhibited delayed PGE2generation in response to IL-1β. IL-1β also stimulated expression of cPLA2and COX-2 only, while constitutive and IL-1β-induced type IIA and type V secretory PLA2s (sPLA2s) expression could not be detected. A COX-2 inhibitor and cPLA2inhibitor markedly suppressed the IL-1β-induced delayed PGE2generation, while a type IIA sPLA2inhibitor failed to affect it. IFN-γ and IL-4 dramatically inhibited the IL-1β-induced delayed PGE2generation; these cytokines apparently suppressed IL-1β-stimulated COX-2 expression and only weakly suppressed cPLA2expression in response to IL-1β. These results indicate that IL-1β-induced delayed PGE2generation in these human fibroblasts mainly depends on de novo induction of COX-2 and cPLA2, irrespective of the constitutive presence of COX-1, and that IFN-γ and IL-4 inhibit IL-1β-induced delayed PGE2generation by suppressing, predominantly, COX-2 expression.