Role of p38 MAPK in Transforming Growth Factor β Stimulation of Collagen Production by Scleroderma and Healthy Dermal Fibroblasts

Transforming growth factor β has been implicated as a mediator of excessive extracellular matrix deposition in scar tissue and fibrosis, including systemic sclerosis. To further characterize the mechanism of collagen gene expression in systemic sclerosis and healthy skin fibroblasts, we examined the role of p38 MAPK signaling in collagen gene regulation by transforming growth factor β. Treatment of dermal fibroblasts with transforming growth factor β resulted in a prolonged activation of p38 MAPK. Furthermore, a specific inhibitor of p38 suppressed transforming growth factor β stimulation of collagen type I mRNA and the α2(I) collagen promoter activity. To further probe the role of p38 in collagen regulation by transforming growth factor β, we utilized an expression vector containing p38α cDNA. Ectopic expression of p38α enhanced COL1A2 promoter activity and potentiated transforming growth factor β stimulation of this promoter. The p38 response element in the COL1A2 promoter overlapped with the previously characterized transforming growth factor β response element. Consistent with these observations, collagen type I mRNA and protein levels were increased in transforming-growth-factor-β-stimulated fibroblasts transduced with an adenoviral vector expressing p38α. To determine the possible role of p38 in abnormal collagen production by systemic sclerosis fibroblasts, p38 protein levels were compared in systemic sclerosis and healthy skin fibroblasts. Both cell types exhibited similar total levels of p38 MAPK and similar kinetics of p38 activation in response to transforming growth factor β. In conclusion, this study demonstrates a costimulatory role for p38 MAPK in transforming growth factor β induction of the collagen type I gene. Expression levels and activation status of p38 are not consistently elevated in systemic sclerosis fibroblasts suggesting that the p38 MAPK pathway is not dysregulated in systemic sclerosis fibroblasts.