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Am J Physiol Lung Cell Mol Physiol 281: L958-L968, 2001;
1040-0605/01 $5.00
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Vol. 281, Issue 4, L958-L968, October 2001

Synergistic effects of tumor necrosis factor-alpha and thrombin in increasing endothelial permeability

Chinnaswamy Tiruppathi*, Tabassum Naqvi*, Raudel Sandoval, Dolly Mehta, and Asrar B. Malik

Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612

Because activation of the coagulation cascade and the generation of thrombin coexist with sepsis and the release of tumor necrosis factor (TNF)-alpha , we determined the effects of TNF-alpha on the mechanism of thrombin-induced increase in endothelial permeability. We assessed Ca2+ signaling in human umbilical vein endothelial cells. In human umbilical vein endothelial cells exposed to TNF-alpha for 2 h, thrombin produced a rise in the intracellular Ca2+ concentration ([Ca2+]i) lasting up to 10 min. In contrast, thrombin alone produced a rise in [Ca2+]i lasting for 3 min, whereas TNF-alpha alone had no effect on [Ca2+]i. Thrombin-induced inositol 1,4,5-trisphosphate generation was not different between control and TNF-alpha -exposed cells. In the absence of extracellular Ca2+, thrombin produced similar increases in [Ca2+]i in both control and TNF-alpha -exposed cells. In TNF-alpha -exposed cells, the thrombin-induced Ca2+ influx after intracellular Ca2+ store depletion was significantly greater and prolonged compared with control cells. Increased Ca2+ entry was associated with an approximately fourfold increase in Src activity and was sensitive to the Src kinase inhibitor PP1. After TNF-alpha exposure, thrombin caused increased tyrosine phosphorylation of junctional proteins and actin stress fiber formation as well as augmented endothelial permeability. These results suggest that TNF-alpha stimulation of endothelial cells results in amplification of the thrombin-induced Ca2+ influx by an Src-dependent mechanism, thereby promoting loss of endothelial barrier function.

store-operated calcium influx; Src tyrosine kinase

* Chinnaswamy Tiruppathi and Tabassum Naqvi contributed equally to this work.




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