Cytokine regulation of beta-adrenergic responses in airway smooth muscle.
Decreased responsiveness to beta-adrenergic receptor agonists is a characteristic feature of human asthma. One explanation for this observation is that cytokines released in the asthmatic airway have direct effects on airway smooth muscle cells that reduce the ability of the cells to relax in response to beta-agonists. This review summarizes data indicating that both inflammatory cytokines, such as IL-1beta and TNF-alpha, and Th2 cytokines, such as IL-13 and IL-5, have the capacity to decrease the ability of cultured airway smooth muscle cells to relax or to generate cyclic AMP in response to beta-agonists, such as isoproterenol. These effects are observed in smooth muscle from human airways and airway smooth muscle of other species. In human airway smooth muscle, the effects of IL-1beta and TNF-alpha appear to be mediated through expression of cyclooxygenase-2, whereas the effect of IL-13 requires activation of the extracellular signal-regulated kinase-mitogen-activated protein kinase pathway. IL-1beta and TNF-alpha also inhibit the ability of beta-agonists to drive airway smooth muscle gene expression through pathways dependent on cyclic AMP response elements. Understanding the mechanistic basis for the effects of these cytokines may prove to be an important step in improving the efficacy of beta-agonists for the treatment of asthma.
Shore
Stephanie A
SA
Physiology Program, Harvard School of Public Health, Boston, Mass 02115, USA.
D000818:Animals; D001249:Asthma / Q000378:metabolism; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism
D016207:Cytokines; D007527:Isoenzymes; D008565:Membrane Proteins; D011943:Receptors, Adrenergic, beta; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases