Transforming growth factor-beta1 suppresses the up-regulation of matrix metalloproteinase-2 by lung fibroblasts in response to tumor necrosis factor-alpha.

摘要

Exposed to inflammatory factors or cytokines, fibroblasts appear to play additional roles beyond the deposition of extracellular matrix. It has been reported that tumor necrosis factor-alpha (TNF-alpha) induces the production of matrix metalloproteinase-2 (MMP-2) and transforming growth factor-beta1 (TGF-beta1) in fibroblasts. In this study, we demonstrated that the active MMP-2 secreted by lung fibroblasts reached the peak level at 12 hours after TNF-alpha treatment, whereas, by adding anti-TGF-beta1 antibody in the culture medium, the MMP-2 production in response to TNF-alpha was maintained at high levels after 24 hours of treatment. We also confirmed that TNF-alpha induced up-regulation of active TGF-beta1 and exogenous TGF-beta1 induced down-regulation of MMP-2 synthesis in lung fibroblasts. Moreover, an increased MMP-2 level was observed in a rat model with pulmonary inflammation and fibrosis induced by bleomycin-A5. This revealed that MMP-2 in the lung reached the peak level when TNF-alpha reached the peak level at the 7th day, and then MMP-2 decreased along with an increase in the TGF-beta1 level. Taken together, our results demonstrate that TNF-alpha induced an increase of MMP-2 and TGF-beta1 in lung fibroblasts, and the TGF-beta1 attenuated the up-regulation of MMP-2. This suggests that MMP-2 secreted from fibroblasts modulated by TNF-alpha/TGF-beta1 might play an important role in pulmonary inflammation and fibrosis.