TGF-BETA AND THE ENDOTHELIUM DURING IMMUNE INJURY

During immune injury, activation of endothelial cells by inflammatory cytokines stimulates leukocyte adhesion to the endothelium, turns the endothelium from an anticoagulant surface to one that is frankly proco agulant, and results in the release of vasoactive mediators and growth factors. Cytokine activation of endothelial cells also results in inc reased endothelial cell TGF-beta 1 synthesis and enhanced activation o f latent TGF-beta, the latter involving a shift of plasmin production from the apical to subendothelial surface. In cytokine-stimulated endo thelial cells, TGF-beta hinders leukocyte adhesion and transmigration via inhibition of IL-8 and E-selectin expression. TGF-beta also profou ndly diminishes cytokine-stimulated inducible nitric oxide synthase pr oduction and instead augments endothelial nitric oxide synthase expres sion. Thus, some of the TGF-beta actions on endothelium during immune activation can viewed as immunosuppressive. TGF-beta also influences m echanisms of vascular remodeling during the healing phase of immune in jury. II stimulates PDGF-B synthesis by endothelial cells, causes bFGF release from subendothelial matrix, and promotes VEGF synthesis by no n-endothelial cells. Together these mediators control angiogenesis, a critical component of the vascular repair phenomenon. Further, endothe lial cell derived PDGF-B and bFGF influence the proliferation and migr ation of neighboring cells. Thus, endothelial cells and TGF-beta actio ns on the endothelium play important roles both during the initial pha se of immune injury and during the later remodeling phase.