Question: 

The transforming growth factor-b-activated kinase 1 (TAK1) is a MAP3K and an AMP-activated protein kinase (AMPK) kinase in some cells. TAK1 promotes inflammation and proliferation in response to TGFb or proinflammatory chemokines. Although TAK1^-/- mice display defects in developmental vasculogenesis, the functional role of TAK1 in endothelial cells has not been investigated in detail.

Methodology and Results: 

Human umbilical vein endothelial cells expressed TAK1. Cytokine stimulation with TNFa and IL-1b, but not TGFb, resulted in the upregulation of COX-2, VCAM- and E-selectin, and IL-1b increased monocyte adhesion to endothelial cells. TAK1 stimulated the phosphorylation of JNK, p38 and IKK, effects that could be prevented by downregulating TAK expression (siRNA) or using oxozeaenol, a pharmacological TAK1 inhibitor. TAK1 knockdown also impaired endothelial cell proliferation, migration and angiogenesisin vitro. Cell proliferation was stimulated by TNFa stimulation, an effect that could be abolished by TAK1 downregulation. Overexpression experiments demonstrated that the TAK1-binding protein1 (TAB1) triggers TAK1 autophosphorylation and subsequent phosphorylation of JNK. In an overexpression system the TAK1-dependent phosphorylation of AMPK could be demonstrated. However, the AMPKa2 can exert a negative feedback on TAK1 function, as in cells transduced with constitutive active AMPKa2, TAB1 expression was decreased. TAB1 expression was increased in AMPKa2 knockout mice.

Conclusion: 

These results demonstrate that TAK1 contributes to inflammation-induced angiogenesis in endothelial cells. The TAK1-mediated activation of AMPK and the AMPK-mediated inhibiton of TAK1 function might serve as a negative feedback mechanism to control inflammation and promote its proangiogenic effects.