Cadherin-5 redistribution at sites of TNF-alpha and IFN-gamma-induced permeability in mesenteric venules

The response of the endothelial permeability barrier in microvascular netwo rks of the rat mesentery to perfused immune inflammatory cytokines tumor ne crosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) was examin ed. TNF-alpha (12.5 U/ml) treatment did not change albumin permeability, bu t in combination with IFN-gamma (20 U/ml), there was a marked increase in t he number of sites of extravascular albumin in postcapillary venules. Endot helial integrity was characterized by cadherin-5 immunoreactivity, which wa s localized to the continuous intercellular junctions of endothelium in art erioles, capillaries, and venules. Perfusion with the combined cytokines sh owed that the increased albumin permeability was dose dependent and correla ted with the focal disorganization of cadherin-5 at intercellular junctions of venular endothelium. No correlation was found between the increase in a lbumin permeability and the localization of intravascular leukocytes or ext ravascular mast cells. These results show that the combination of TNF-alpha and IFN-gamma induces an endothelial phenotype with focal loss of cadherin -5 intercellular adhesion, which, in part, facilitates passage of blood mac romolecules and cells to the interstitium.