Mitogenic effects of cytokines on smooth muscle are critically dependent on protein kinase A and are unmasked by steroids and cyclooxygenase inhibitors.
Excessive smooth muscle growth occurs within the context of inflammation associated with certain vascular and airway diseases. The inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha) have been shown previously to inhibit mitogen-stimulated smooth muscle growth through a mechanism presumed to be dependent on the induction of cyclooxygenase-2, prostaglandins, and activation of the cAMP-dependent protein kinase (PKA). Using both molecular and pharmacological strategies, we demonstrate that the mitogenic effects of IL-1beta and TNF-alpha on cultured human airway smooth muscle (ASM) cells are tightly regulated by PKA activity. Suppression of induced PKA activity by either corticosteroids or cyclooxygenase inhibitors converts the cytokines from inhibitors to enhancers of mitogen-stimulated ASM growth, and biological variability in the capacity to activate PKA influences the modulatory effect of cytokines. Promitogenic effects of IL-1beta are associated with delayed increases in p42/p44 and phosphoinositide-3 kinase activities, suggesting a role for induced autocrine factors. These findings suggest a mechanism by which mainstream therapies such as corticosteroids or cyclooxygenase inhibitors could fail to address or exacerbate the pathogenic smooth muscle growth that occurs in obstructive airway and cardiovascular diseases.
Misior
Anna M
AM
Wake Forest University Health Sciences Center, Center for Human Genomics, Medical Center Blvd, Winston-Salem NC 27157, USA.
Yan
Huandong
H
Pascual
Rodolfo M
RM
Deshpande
Deepak A
DA
Panettieri
Reynold A
RA
Penn
Raymond B
RB
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000502:physiology; D008934:Mitogens / Q000235:genetics / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism*
D000305:Adrenal Cortex Hormones; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D053583:Interleukin-1beta; D008934:Mitogens; D017868:Cyclic AMP-Dependent Protein Kinases