Regulatory features of interleukin-1β-mediated prostaglandin E₂ synthesis in airway smooth muscle

Abstract

Exposure of airway smooth muscle (ASM) cells to the cytokine IL-1beta results in an induction of PGE2 synthesis that affects numerous cell functions. Current dogma posits induction of COX-2 protein as the critical, obligatory event in cytokine-induced PGE2 production, although PGE2 induction can be inhibited without a concomitant inhibition of COX-2. To explore other putative regulatory features we examined the role of phospholipase A2 (PLA2) and PGE synthase (PGES) enzymes in IL-1beta-induced PGE2 production. Treatment of human ASM cultures with IL-1beta caused a time-dependent induction of both cytosolic PLA2 (cPLA2) and microsomal PGES (mPGES) similar to that observed for COX-2. Regulation of COX-2 and mPGES induction was similar, being significantly reduced by inhibition of p42/p44 or p38, whereas cPLA2 induction was only minimally reduced by inhibition of p38 or PKC. COX-2 and mPGES induction was subject to feed-forward regulation by PKA, whereas cPLA2 induction was not. SB-202474, an SB-203580 analog lacking the ability to inhibit p38 but capable of inhibiting IL-1beta-induced PGE2 production, was effective in inhibiting mPGES but not COX-2 or cPLA2 induction. These data suggest that although COX-2, cPLA2, and mPGES are all induced by IL-beta in human ASM cells, regulatory features of cPLA2 are dissociated, whereas those of COX-2 and mPGES are primarily associated, with regulation of PGE2 production. mPGES induction and, possibly, cPLA2 induction appear to cooperate with COX-2 to determine IL-1beta-mediated PGE2 production in human ASM cells.

Mitogenic Effects of Cytokines on Smooth Muscle Are Critically Dependent on Protein Kinase A and Are Unmasked by Steroids and Cyclooxygenase Inhibitors

“…If the principal source of cytokine-stimulated PKA activity responsible for the suppressive effect on EGF-stimulated growth is COX-2-derived PGE 2 , we hypothesized that agents capable of inhibiting the induction of COX-2 protein or activity or inhibiting other enzymes important in cytokine-induced PGE 2 production (Pascual et al, 2006) would have similar effects. This proved to be the case, because pretreatment of naive ASM cells with indomethacin (an inhibitor of COX activity), SB203580 or bisindolylmaleimide I (Bis I) (inhibitors of p38 and protein kinase C, respectively) shown previously to inhibit induction of COX-2 and mPGES1 by IL-1␤ in ASM cells (Pascual et al, 2006) also increased IL-1␤-stimulated growth and converted IL-1␤ from an inhibitor to an enhancer of EGF-stimulated growth ( Fig.…”

“…This proved to be the case, because pretreatment of naive ASM cells with indomethacin (an inhibitor of COX activity), SB203580 or bisindolylmaleimide I (Bis I) (inhibitors of p38 and protein kinase C, respectively) shown previously to inhibit induction of COX-2 and mPGES1 by IL-1␤ in ASM cells (Pascual et al, 2006) also increased IL-1␤-stimulated growth and converted IL-1␤ from an inhibitor to an enhancer of EGF-stimulated growth ( Fig. 2A).…”

“…2A). Pretreatment with the corticosteroid FLU, known to be a strong suppressor of cytokine-induced prostanoid synthesis (Vlahos and Stewart, 1999;Pascual et al, 2006), also caused IL-1␤ to enhance EGF-stimulated growth. The magnitude of effects of indomethacin, SB203580, Bis I, or FLU corresponded to the efficacy of each inhibitor in inhibiting EGF ϩ IL-1␤-induced PKA activation, which was determined by characterizing the reversal of the shift of the PKA substrate VASP from the 50-kDa species to the 46-kDa species (Fig.…”

“…IL-1␤ and (to a lesser extent) TNF-␣ can induce COX-2 protein and PGE 2 generation in ASM cells, and cotreatment with serum or EGF greatly increases this induction (Pascual et al, , 2006. For this reason, and given the observation that exogenous PGE 2 inhibits ASM growth, COX-2-dependent PGE 2 production has been assumed to mediate inhibition of ASM growth by these cytokines.…”

Timely interaction between prostaglandin and chemokine signaling is a prerequisite for successful fertilization

“…Thus, IL-1␤ is a strong candidate molecule for the stimulation of Ccl gene expression in the cumulus. In this respect, it is interesting that the expression Il1b was increased in Ptger2 Ϫ/Ϫ cumuli (Table S1) Moreover, because IL-1␤ also has been shown to induce the expression of Ptgs2 and Ptges (PGE synthase gene) in various cells (33,34), PGE 2 synthesis in cumulus cells may be resumed by the action of IL-1␤. If this mechanism were operating, then IL-1␤ could determine the timely interaction between PGE 2 and CCL actions in the cumulus ECM assembly.…”