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Tumor necrosis factor-alpha inhibits growth factor-mediated cell proliferation through SHP-1 activation in
Hironori Nakagami1, Tai-Xing Cui, Masaru Iwai
1Department of Medical Biochemistry, Ehime University Medical School, Ehime, Japan.
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-alpha (TNF-alpha) 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-alpha (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-alpha activated SHP-1. Importantly, overexpression of dominant-negative SHP-1 attenuated the effect of TNF-alpha on thymidine incorporation and c-fos promoter activity. In addition, TNF-alpha 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-alpha. Taken together, our results suggested that TNF-alpha inhibited growth factor-mediated cell proliferation through SHP-1 activation.
Insights
Tumor necrosis factor-alpha (TNF-alpha) inhibits endothelial cell proliferation by activating Src homology 2-containing protein-tyrosine phosphatase 1 (SHP-1). This activation blocks growth factor signaling pathways, reducing cell growth.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Src homology 2-containing protein-tyrosine phosphatase 1 (SHP-1) dephosphorylates tyrosine kinases, regulating signal transduction.
- Tumor necrosis factor-alpha (TNF-alpha) is a key inflammatory cytokine with diverse cellular effects.
Purpose of the Study:
- To investigate the role of SHP-1 in endothelial cells stimulated by TNF-alpha.
- To elucidate the mechanism by which TNF-alpha affects growth factor-induced endothelial cell proliferation.
Main Methods:
- Assessed thymidine incorporation and c-fos promoter activity in response to growth factors and TNF-alpha.
- Confirmed endogenous SHP-1 expression and TNF-alpha-induced SHP-1 activation in bovine aortic endothelial cells.
- Utilized dominant-negative SHP-1 overexpression to study its functional role.
Main Results:
- TNF-alpha attenuated vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF)-induced thymidine incorporation and c-fos promoter activity.
- TNF-alpha activated SHP-1 in endothelial cells.
- Overexpression of dominant-negative SHP-1 blocked TNF-alpha's inhibitory effects on proliferation and c-fos activity.
- TNF-alpha inhibited VEGF- and EGF-induced extracellular signal-regulated kinase (ERK) phosphorylation, an effect prevented by dominant-negative SHP-1.
Conclusions:
- TNF-alpha inhibits growth factor-mediated endothelial cell proliferation.
- SHP-1 activation by TNF-alpha is the key mechanism underlying this inhibition.
- SHP-1 mediates the suppressive effects of TNF-alpha on growth factor signaling pathways, including ERK phosphorylation.