Received for publication August 3, 2007.
Revised November 8, 2007.
Accepted for publication November 9, 2007.

Mitogenic effects of cytokines on smooth muscle are critically dependent on protein kinase A and are unmasked by steroids and cyclooxygenase inhibitors

Abstract

Excessive smooth muscle growth occurs within the context of inflammation associated with certain vascular and airway diseases. The inflammatory cytokines IL-1 and TNF- have previously been shown to inhibit mitogen-stimulated smooth muscle growth, through a mechanism presumed dependent on the induction of cyclooxygenase-2, prostaglandins, and activation of the cAMP-dependent protein kinase (PKA). Using both molecular and pharmacologic strategies, we demonstrate that the mitogenic effects of IL-1 and TNF- 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 biologic variability in the capacity to activate PKA influences the modulatory effect of cytokines. Pro-mitogenic effects of IL-1 are associated with delayed increases in p42/p44 and PI3K 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.

Key words: Prostanoid, NGF/EGF, Interleukins, Tumor necrosis factor, Gs family, cAMP, Protein Kinase A, Cyclooxygenases, Tissue hypertrophy