Steffel J, Arnet C, Akhmedov A, Iseli S M, Lüscher T F, Tanner F C
Cardiovascular Research, Physiology Institute, University of Zürich, and Cardiology, Cardiovascular Center, University Hospital Zürich, Switzerland.
J Thromb Haemost. 2006 Nov;4(11):2452-60. doi: 10.1111/j.1538-7836.2006.02175.x. Epub 2006 Aug 25.
Histamine plays an important role in vascular disease. Tissue factor (TF) expression is induced in vascular inflammation and acute coronary syndromes.
This study examined the effect of histamine on tumor necrosis factor-alpha- (TNF-alpha-) vs. thrombin-induced endothelial TF expression.
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.
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.
组胺在血管疾病中起重要作用。在血管炎症和急性冠状动脉综合征中会诱导组织因子（TF）表达。
本研究检测了组胺对肿瘤坏死因子-α（TNF-α）和凝血酶诱导的内皮细胞TF表达的影响。
组胺（10⁻⁸ - 10⁻⁵ mol/L）、TNF-α（5 ng/mL）和凝血酶（1 U/mL）可诱导人内皮细胞表达TF。虽然TNF-α和凝血酶诱导的TF表达相同，但组胺使TNF-α诱导的表达增加7.0倍，而使凝血酶诱导的表达仅增加2.6倍。TF活性也有类似反应。H1受体拮抗剂美吡拉敏可消除这些作用。在mRNA水平也观察到组胺的差异增强作用。组胺诱导的p38激活先于对TNF-α和凝血酶的微弱二次激活。组胺诱导的c-Jun氨基末端激酶（JNK）激活后，对TNF-α有强烈的二次激活，对凝血酶的激活较弱。用SP600125选择性抑制这种二次JNK激活，可使组胺加TNF-α诱导的TF降低67%，但使组胺加凝血酶诱导的TF仅降低32%。组胺对TNF-α和凝血酶诱导的血管细胞黏附分子1（VCAM-1）表达的增强程度相似。与此观察结果一致，VCAM-1对TNF-α和凝血酶的诱导由p38介导，而非JNK。
组胺对TNF-α和凝血酶诱导的TF表达及活性有差异增强作用，由H1受体介导，发生在mRNA水平，且与JNK的差异激活有关。
