RESUMEN
BACKGROUND: Histamine plays an important role in vascular disease. Tissue factor (TF) expression is induced in vascular inflammation and acute coronary syndromes. OBJECTIVES: This study examined the effect of histamine on tumor necrosis factor-alpha- (TNF-alpha-) vs. thrombin-induced endothelial TF expression. METHODS AND RESULTS: Histamine (10(-8)-10(-5) mol L-1), TNF-alpha (5 ng mL-1), and thrombin (1 U mL-1) induced TF expression in human endothelial cells. Although TF expression by TNF-alpha and thrombin was identical, histamine augmented TNF-alpha-induced expression 7.0-fold, but thrombin-induced expression only 2.6-fold. Similar responses occurred with TF activity. The H1-receptor antagonist mepyramine abrogated these effects. Differential augmentation by histamine was also observed at the mRNA level. Histamine-induced p38 activation preceded a weak second activation to both TNF-alpha and thrombin. Histamine-induced c-Jun NH2-terminal kinase (JNK) activation was followed by a strong second activation to TNF-alpha, and less to thrombin. Selective inhibition of this second JNK activation by SP600125 reduced TF induction to histamine plus TNF-alpha by 67%, but to histamine plus thrombin by only 32%. Histamine augmented TNF-alpha- and thrombin-induced vascular cell adhesion molecule 1 (VCAM-1) expression to a similar extent. Consistent with this observation, VCAM-1 induction to TNF-alpha and thrombin was mediated by p38, but not by JNK. CONCLUSIONS: Histamine differentially augments TNF-alpha- vs. thrombin-induced TF expression and activity, which is mediated by the H1-receptor, occurs at the mRNA level, and is related to differential JNK activation.