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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:238.)
© 2002 American Heart Association, Inc.

Vascular Biology

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

Hironori Nakagami; Tai-Xing Cui; Masaru Iwai; Tetsuya Shiuchi; Yuko Takeda-Matsubara; Lan Wu; Masatsugu Horiuchi

From the Department of Medical Biochemistry, Ehime University Medical School, Ehime, Japan.

Correspondence to Masatsugu Horiuchi, MD, PhD, Department of Medical Biochemistry, Ehime University School of Medicine, Shitsukawa, Shigenobu, Onsen-gun, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

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- (TNF-) 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- (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- activated SHP-1. Importantly, overexpression of dominant-negative SHP-1 attenuated the effect of TNF- on thymidine incorporation and c-fos promoter activity. In addition, TNF- attenuated vascular endothelial growth factor– and epidermal growth factor–induced extracellular signal–regulated kinase phosphorylation, whereas overexpression of dominant-negative SHP-1 prevented this inhibitory effect of TNF-. Taken together, our results suggested that TNF- inhibited growth factor–mediated cell proliferation through SHP-1 activation.

Key Words: SHP-1 • vascular endothelial growth factor • epidermal growth factor • tumor necrosis factor- • endothelial cells

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