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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 5, May, 2001 633-639

Interleukin-1beta and Rhinovirus Sensitize Adenylyl Cyclase in Human Airway Smooth-Muscle Cells

Charlotte K. Billington, Rodolfo M. Pascual, Michael L. Hawkins, Raymond B. Penn, and Ian P. Hall

Division of Therapeutics & Institute of Cell Signalling, and Public Health Laboratory, University Hospital of Nottingham, Nottingham, United Kingdom; and Departments of Medicine, Division of Critical Care, Pulmonary, Allergic, and Immunological Diseases, and Microbiology & Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania

Rhinovirus (RV) is a major cause of wheezing in asthmatics and has been reported to cause beta 2 adrenergic receptor hyporesponsiveness in human airway smooth muscle (HASM) via cellular secretion of interleukin (IL)-1beta . We studied the effects of IL-1beta and RV on cyclic adenosine monophosphate (cAMP) production in HASM cells. Chronic incubation with IL-1beta or RV caused a significant increase (~ 3- and ~ 2-fold, respectively) in forskolin (FSK)-stimulated cAMP production, suggesting a sensitization of adenylyl cyclase (AC). The observed augmentation of FSK-stimulated cAMP formation by IL-1beta was completely abrogated by pretreatment with an IL-1 receptor antagonist or cycloheximide, demonstrating that the effect is mediated via the IL-1 receptor 1 (IL-1R1) and that de novo protein synthesis is required. In contrast, RV-induced AC sensitization was not mediated via the IL-1R1 but was observed to be protein kinase C-dependent. We suggest that the sensitization of AC observed after exposure to IL-1beta or RV infection is a cellular defense mechanism to promote pathways that induce relaxation in the inflamed airway.

Abbreviations: adenylyl cyclase, AC; beta 2 adrenergic receptor, beta 2AR; bisindoylmaleimide I, Bis I; cyclic adenosine monophosphate, cAMP; cyclooxygenase, COX; forskolin, FSK; human airway smooth muscle, HASM; infectious dose required to infect 50% of cell cultures inoculated with virus, ID50; interleukin, IL; IL-1 receptor antagonist, IL-1ra; prostaglandin, PG; protein kinase, PK; pertussis toxin, PTX; rhinovirus, RV; standard error of the mean, SEM.




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