Does TNF-alpha directly increase endothelial cell monolayer permeability?

The effects of dexamethasone (DEX) and N omega-nitro-L-arginine methyl ester (L-NAME) on the tumour necrosis factor-alpha (TNF-alpha)-induced increase in permeability of human umbilical vein endothelial cell (HUVEC) monolayer to [125I] labelled bovine serum albumin (BSA) were examined. Preincubation of HUVEC monolayers with DEX (1 microM, 2h) completely abolished the effect of TNF-alpha (5 ng/ml, 18 h). Administration of DEX 2 h after TNF-alpha also reduced the effect of TNF-alpha while L-NAME (5 ng/ml, 1 mM, 18 h) had no significant effect. The observed inhibition of the TNF-alpha-induced permeability increase on preincubation with DEX would suggest a role for nitric oxide (NO) in mediating the permeability response. However, this is not confirmed by the experiments with L-NAME. The inhibition caused by DEX administered after TNF-alpha would suggest alternative mechanisms by which DEX may be acting in addition to inhibition of NO synthase induction.