Interleukin-1beta and rhinovirus sensitize adenylyl cyclase in human airway smooth-muscle cells.
Rhinovirus (RV) is a major cause of wheezing in asthmatics and has been reported to cause beta2 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 (approximately 3- and approximately 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.
Billington
C K
CK
Division of Therapeutics & Institute of Cell Signalling, and Public Health Laboratory, University Hospital of Nottingham, Nottingham, United Kingdom.
Pascual
R M
RM
Hawkins
M L
ML
Penn
R B
RB
Hall
I P
IP
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005246:Feedback; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D010850:Picornaviridae Infections / Q000201:enzymology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I; D012229:Rhinovirus / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000494:pharmacology; D014132:Trachea; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D011500:Protein Synthesis Inhibitors; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D012795:Sialoglycoproteins; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D003513:Cycloheximide; D000242:Cyclic AMP; D011493:Protein Kinase C; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases