TNF is a primary inflammatory cytokine with profound effects on endothelial cells. TNF activates a proinflammatory, prothrombotic, and proangiogenic program in endo-
thelial cells (1-3). Endothelial cells express both the p55 and the p75 TNF receptor. The p75 receptor is most abundant on the cell; p55 is mostly localized in the Golgi apparatus and in cytoplasmic vacuoles (47,48). Endothelial cells respond to TNF via the p55 receptor, and p75 amplifies the response to low concentrations of the agonist by a process referred to as ligand passing (49-51). TNF regulates the life-span of endothelial cells and angiogenesis with seemingly contradictory actions. TNF is not growth factor for endothelial cells, but it induces endothelial cell migration in vitro and angiogenesis in vitro and in vivo (reviewed in ref. 3). These functions may be indirect. TNF induces production of the secreted protein B.61, which functions as an endothelial chemoattractant and angiogenic factor by acting as the ligand for the eck tyrosine kinase receptor (52,53). Platelet-activating factor (PAF; see Section 4.1.) and nitric oxide (NO; see Section 4.2.) are two other molecules produced by endothelium after TNF challenge, which contribute to the angiogenic effect of the cytokine (54,55). Finally, TNF upregulates the expression of urokinase-type plasminogen activator (uPA) and its specific receptor (uPAR), thus favoring the degradation of proteins of extracellular matrix, a key step in angiogenesis (reviewed in refs. 1,2, 56). uPAR binds to the inactive form of uPA, and converts it into the active form, which in turns is able to degrade extracellular matrix, and to activate matrix metalloproteinases. The upregulation of uPAR is required for the in vitro angio-genesis of human microvascular endothelial cells stimulated by vascular endothelial growth factor (VEGF)-A or bFGF (56).
Furthermore, other molecules cloned as TNF-inducible genes in endothelial cells may be relevant to vasculogenesis or angiogenesis (57). A20 is a zinc-finger transcription factor that may be important in protection of endothelial cells and other cell types against TNF toxicity. B94 is a gene of unknown function, expressed in a complex way during vasculogenesis.
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