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

¹Department of Internal Medicine and Center for Human Genomics, Wake Forest University Health Sciences Center, Winston-Salem, North Carolina; and ²Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Submitted 3 October 2005 ; accepted in final form 21 October 2005

Exposure of airway smooth muscle (ASM) cells to the cytokine IL-1 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-1-induced PGE₂ production. Treatment of human ASM cultures with IL-1 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-1-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- 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-1-mediated PGE₂ production in human ASM cells.

cyclooxygenase-2; phospholipase A₂; prostaglandin E₂ synthase

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