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Am J Physiol Lung Cell Mol Physiol 281: L1425-L1435, 2001;
1040-0605/01 $5.00
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Vol. 281, Issue 6, L1425-L1435, December 2001

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

Rodolfo M. Pascual1, Charlotte K. Billington2, Ian P. Hall2, Reynold A. Panettieri Jr.3, James E. Fish1, Stephen P. Peters1, and Raymond B. Penn4

1 Division of Critical Care, Pulmonary, Allergic, and Immunological Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University; 2 Department of Therapeutics, Institute of Cell Signaling, University Hospital of Nottingham, Nottingham, United Kingdom NG7 2UH; 3 Division of Pulmonary and Critical Care, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104; and 4 Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Numerous in vitro and in vivo studies have implicated the cytokines interleukin-1beta (IL-1beta ) and tumor necrosis factor-alpha (TNF-alpha ) as mediators of airway inflammation and therefore potentially important substances in the pathogenesis of asthma. In this study, we examined the mechanisms by which IL-1beta and TNF-alpha affect inhibition of cell growth, G protein-coupled receptor (GPCR) desensitization, and the recently reported adenylyl 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 E2 (PGE2) induction, whereas COX-2 induction appears to be required for both growth inhibition and GPCR desensitization. However, GPCR desensitization was highly dependent on the presence of EGF during chronic treatment with cytokines, which could be explained by a synergistic effect of EGF on cytokine-mediated COX-2 and PGE2 induction. Interestingly, various agents (including inhibitors of p42/p44 and p38 mitogen-activated protein kinase signaling) were significantly more effective in inhibiting cytokine-mediated PGE2 induction, GPCR desensitization, and cell growth inhibition than in inhibiting COX-2 induction. These data demonstrate disparity in the requirement and sufficiency of COX-2 induction in promoting different functional effects of IL-1beta and TNF-alpha in HASM.

interleukin-1beta ; tumor necrosis factor-alpha ; adenylyl cyclase; sensitization


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