Interferon-gamma and interleukin 4 inhibit interleukin 1 beta-induced delayed prostaglandin E-2 generation through suppression of cyclooxygenase-2 expression in human fibroblasts

Interleukin (IL-)1 stimulates prostaglandin E-2 (PGE(2)) generation in fibr oblasts, and preferential couplings between particular phospholipase A(2) ( PLA(2)) and cyclooxygenase (COX) isozymes are implicated with IL-1-induced delayed PGE(2) generation. The regulatory effects of interferon (IFN)-gamma and IL-4 on IL-1 beta-induced COX, PLA(2) isoforms expression and terminal delayed PGE(2) generation were examined in three types of human fibroblast s, These human fibroblasts constitutively expressed cytosolic PLA(2) (cPLA( 2)) and COX-1 enzymes, and exhibited delayed PGE(2) generation in response to IL-1 beta, IL-1 beta also stimulated expression of cPLA(2), and COX-2 on ly, while constitutive and IL-1 beta-induced type IIA and type V secretory PLA(2)s (sPLA(2)s) expression could not be detected. A COX-2 inhibitor and cPLA(2) inhibitor markedly suppressed the IL-1 beta-induced delayed PGE(2) generation, while a type IIA sPLA(2) inhibitor failed to affect it. IFN-gam ma and IL-4 dramatically inhibited the IL-1 beta-induced delayed PGE(2) gen eration; these cytokines apparently suppressed IL-1 beta-stimulated COX-2 e xpression and only weakly suppressed cPLA(2) expression in response to IL-1 beta. These results indicate that IL-1 beta-induced delayed PGE(2) generat ion in these human fibroblasts mainly depends on de novo induction of COX-2 and cPLA(2), irrespective of the constitutive presence of COX-1, and that IFN-gamma and IL-4 inhibit IL-1 beta-induced delayed PGE(2) generation by s uppressing, predominantly, COX-2 expression. (C) 2000 Academic Press.