Mechanisms of cytokine effects on G protein-coupled receptor-mediated signaling in airway smooth muscle

Numerous in vitro and in vivo studies have implicated the cytokines interle ukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) as medi ators of airway inflammation and therefore potentially important substances in the pathogenesis of asthma. In this study, we examined the mechanisms b y which IL-1 beta and TNF-alpha affect inhibition of cell growth, G protein -coupled receptor (GPCR) desensitization, and the recently reported adenyly l cyclase sensitization in human airway smooth muscle (HASM) cultures. Our findings demonstrate that adenylyl cyclase sensitization is independent of cytokine-mediated cyclooxygenase type 2 (COX-2) and prostaglandin E-2 (PGE( 2)) induction, whereas COX-2 induction appears to be required for both grow th inhibition and GPCR desensitization. However, GPCR desensitization was h ighly dependent on the presence of EGF during chronic treatment with cytoki nes, which could be explained by a synergistic effect of EGF on cytokine-me diated COX-2 and PGE(2) induction. Interestingly, various agents (including inhibitors of p42/p44 and p38 mitogen-activated protein kinase signaling) were significantly more effective in inhibiting cytokine-mediated PGE(2) in duction, GPCR desensitization, and cell growth inhibition than in inhibitin g COX-2 induction. These data demonstrate disparity in the requirement and sufficiency of COX-2 induction in promoting different functional effects of IL-1 beta and TNF-alpha in HASM.