Regulatory features of interleukin-1β-mediated prostaglandin E 2 synthesis in airway smooth muscle

• Published in: American journal of physiology. Lung cellular and molecular physiology 2006-03, Vol.290 (3), p.L501-L508
• Main Authors: Pascual, Rodolfo M., Carr, Elizabeth M., Seeds, Michael C., Guo, Manhong, Panettieri, Reynold A., Peters, Stephen P., Penn, Raymond B.
• Format: Article
• Language: English
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00420.2005

Exposure of airway smooth muscle (ASM) cells to the cytokine IL-1β results in an induction of PGE 2 synthesis that affects numerous cell functions. Current dogma posits induction of COX-2 protein as the critical, obligatory event in cytokine-induced PGE 2 production, although PGE 2 induction can be inhibited without a concomitant inhibition of COX-2. To explore other putative regulatory features we examined the role of phospholipase A 2 (PLA 2 ) and PGE synthase (PGES) enzymes in IL-1β-induced PGE 2 production. Treatment of human ASM cultures with IL-1β caused a time-dependent induction of both cytosolic PLA 2 (cPLA 2 ) 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 cPLA 2 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 cPLA 2 induction was not. SB-202474, an SB-203580 analog lacking the ability to inhibit p38 but capable of inhibiting IL-1β-induced PGE 2 production, was effective in inhibiting mPGES but not COX-2 or cPLA 2 induction. These data suggest that although COX-2, cPLA 2 , and mPGES are all induced by IL-β in human ASM cells, regulatory features of cPLA 2 are dissociated, whereas those of COX-2 and mPGES are primarily associated, with regulation of PGE 2 production. mPGES induction and, possibly, cPLA 2 induction appear to cooperate with COX-2 to determine IL-1β-mediated PGE 2 production in human ASM cells.