Interferon-γ and interleukin 4 inhibit interleukin 1β-induced delayed prostagilandin E₂ generation through suppression of cyclooxugenase-2 expression in human fibroblasts

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 PGE₂ generation. The regulatory effects of interferon (IFN)-γ and IL-4 on IL-1β-induced COX, PLA₂ isoforms expression and terminal delayed PGE₂ generation were examined in three types of human fibroblasts. These human fibroblasts constitutively expressed cytosolic PLA₂ (cPLA₂) and COX-1 enzymes, and exhibited delayed PGE₂ generation in response to IL-1β. IL-1β also stimulated expression of cPLA₂ and 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 cPLA₂ inhibitor markedly suppressed the IL-1β-induced delayed PGE₂ generation, while a type IIA sPLA₂ inhibitor failed to affect it. IFN-γ and IL-4 dramatically inhibited the IL-1β-induced delayed PGE₂ generation; these cytokines apparently suppressed IL-1β-stimulated COX-2 expression and only weakly suppressed cPLA2 expression in response to IL-1β. These results indicate that IL-1β-induced delayed PGE₂ generation 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 PGE₂ generation by suppressing, predominantly, COX-2 expression. (C) 2000 Academic Press.