Summary. 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‐α‐ (TNF‐α‐) vs. thrombin‐induced endothelial TF expression. Methods and results: Histamine (10−8–10−5 mol L−1), TNF‐α (5 ng mL−1), and thrombin (1 U mL−1) induced TF expression in human endothelial cells. Although TF expression by TNF‐α and thrombin was identical, histamine augmented TNF‐α‐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‐α and thrombin. Histamine‐induced c‐Jun NH2‐terminal kinase (JNK) activation was followed by a strong second activation to TNF‐α, and less to thrombin. Selective inhibition of this second JNK activation by SP600125 reduced TF induction to histamine plus TNF‐α by 67%, but to histamine plus thrombin by only 32%. Histamine augmented TNF‐α‐ and thrombin‐induced vascular cell adhesion molecule 1 (VCAM‐1) expression to a similar extent. Consistent with this observation, VCAM‐1 induction to TNF‐α and thrombin was mediated by p38, but not by JNK. Conclusions: Histamine differentially augments TNF‐α‐ 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.
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