Tumor Necrosis Factor-α Inhibits Growth Factor–Mediated Cell Proliferation Through SHP-1 Activation in Endothelial Cells

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Abstract
Src homology 2–containing protein-tyrosine phosphatase 1 (SHP-1) is known to regulate signal transduction through the dephosphorylation of tyrosine kinases. In this study, we addressed the role of SHP-1 under tumor necrosis factor-α (TNF-α) stimulation in endothelial cells. The addition of recombinant vascular endothelial growth factor (50 ng/mL) or epidermal growth factor (50 ng/mL) significantly increased thymidine incorporation and c-fos promoter activity, whereas TNF-α (5 ng/mL) attenuated these effects in human or bovine aortic endothelial cells. In bovine aortic endothelial cells, we confirmed endogenous SHP-1 expression and that TNF-α activated SHP-1. Importantly, overexpression of dominant-negative SHP-1 attenuated the effect of TNF-α on thymidine incorporation and c-fos promoter activity. In addition, TNF-α attenuated vascular endothelial growth factor– and epidermal growth factor–induced extracellular signal–regulated kinase phosphorylation, whereas overexpression of dominant-negative SHP-1 prev...