Regulation of Airway Smooth Muscle Proliferation: Cytokine-, Glucocorticoid-, and pKa-Dependent Mechanisms

Abstract

Increased mass of airway smooth muscle (ASM) is an important pathogenic mechanism in the obstructive airway disease asthma. Increased volume of ASM has been attributed to both smooth muscle hyperplasia and hypertrophy, and is thought to be driven by increased levels of mitogens and inflammatory mediators in the airway. The effects of polypeptide growth factors and G protein coupled receptor (GPCR) ligands on ASM proliferation have been extensively explored, however regulation of growth by the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α has not been well characterized. Both IL-1β and TNF-α, alone or in combination, have been shown to decrease proliferation of human ASM in vitro stimulated by a variety of growth factors or GPCR agonists and the effect is associated with the ability of the cytokines to induce cyclooxygenase (COX)-2 expression, production of prostaglandin E2 (PGE2), and increase cAMP levels. Because cAMP-dependent protein kinase (PKA) is the primary cAMP effector, it has been assumed to mediate the antimitogenic effects of IL-1β and TNF-α. Even though the role for COX-2 and PGE2 in the anti-mitogenic effects of the cytokines is assumed based on association, no evidence directly implicating PKA exists due to lack of effective and specific inhibitors of PKA in intact cells.