IL-1 beta alters beta-adrenergic receptor adenylyl cyclase system function in human airway epithelial cells.
Inflammatory cells release a variety of cytokines, including interleukin (IL)-1 beta, into the airway in asthma. This study examined the effects of human IL-1 beta on the function of the beta-adrenergic receptor (beta AR)-adenylyl cyclase (AC) system in BEAS-2B cells, a human airway epithelial cell line. IL-1 beta markedly increased beta AR density (Bmax; P < 0.001) primarily by increasing the percentage of the beta 2AR subtype (from 67 to 91%; P < 0.001). Bmax increased monotonically over time in response to 200 pM IL-1 beta and was approximately 2.5-fold greater than control cells between 36 and 42 h. In contrast, the concentration response of Bmax to IL-1 beta given for 18 h was biphasic. Bmax increased with IL-1 beta concentrations from 2 to 200 pM, but, at > 200 pM, it decreased progressively toward control values. IL-1 beta-induced increases in Bmax with IL-1 beta were associated with approximately threefold increases in beta 2 AR mRNA and were blocked by the protein synthesis inhibitor cycloheximide. Despite the marked increase in Bmax, however, IL-1 beta depressed adenosine 3',5'-cyclic monophosphate (cAMP) responses to isoproterenol and forskolin, a direct activator of AC (P < 0.001 by analysis of variance for both). The inhibitory effect of IL-1 beta on cAMP production appeared to be explained by increases in the activity of an inhibitory GTP binding protein because IL-1 beta treatment increased the activity of a pertussis toxin ADP-ribosylated Gi alpha protein by approximately 2.5-fold; and pretreatment of intact cells with pertussis toxin inhibited the effect of IL-1 beta on cAMP production. These data indicate that IL-1 beta-mediated changes in the beta AR-AC system function in airway epithelial cells are complex and involve expression of receptor protein, GTP binding protein, and possibly AC itself. Increases in IL-1 beta may contribute to abnormalities in airway function in subjects with asthma.
Kelsen
S G
SG
Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Anakwe
O
O
Aksoy
M O
MO
Reddy
P J
PJ
Dhanasekaran
N
N
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000704:Analysis of Variance; D001980:Bronchi / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004848:Epithelium; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D009243:NAD / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011943:Receptors, Adrenergic, beta / Q000096:biosynthesis*; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D007375:Interleukin-1; D011943:Receptors, Adrenergic, beta; D018343:Receptors, Adrenergic, beta-2; D009243:NAD; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases