TGF-BETA-1 MODULATES HUMAN AIRWAY SMOOTH-MUSCLE CELL-PROLIFERATION INDUCED BY MITOGENS

Asthma is a disease of airway inflammation and bronchoconstriction tha t results in airway smooth-muscle cell hypertrophy and hyperplasia. Th e underlying mechanisms that induce myocyte proliferation remain unkno wn. Evidence suggests that cytokines such as transforming growth facto r (TGF)-beta 1 may play a role in modulating this process. In this stu dy, we examined the effects of TGF-beta 1 on human airway smooth-muscl e (HASM) cell proliferation. We found that treatment of HASM cells wit h TGF-beta 1 inhibited epidermal growth factor (EGF)- and thrombin-ind uced DNA synthesis. This inhibition was both dose and time dependent. We then investigated whether these effects are mediated through activa tion of mitogen-activated protein kinase (MAP kinase), an enzyme that is thought to play a central role in the regulation of cell proliferat ion. We found that MAP kinase activation induced by EGF was not modula ted by TGF-beta 1, despite TGF-beta 1 inhibiting EGF-induced HASM cell growth. These data suggest that TGF-beta 1 inhibits mitogen-induced H ASM cell proliferation, but does so downstream from MAP kinase activat ion, or via a parallel pathway that is independent of MAP kinase activ ation.