Nielson Christopher P, Wingett Denise
Medical Research Service 151, Department of Veterans Affairs Medical Center, 500 W. First Street, Boise, ID 83702, USA.
Immunology. 2002 Apr;105(4):430-40. doi: 10.1046/j.1365-2567.2002.01387.x.
CD40 ligand (CD40L) expression is now recognized to contribute in the pathogenesis of vascular disease. Because increased CD40L has been associated with myocardial infarction, effects of endothelial cells and cAMP with respect to CD40L regulation may be of clinical relevance. In the present study, endothelial cells are shown to markedly increase CD40L on naïve CD4+ T cells with a more modest effect on memory T cells. Furthermore, the addition of dibutyryl cyclic AMP (dbcAMP) synergistically increased naïve cell CD40L but inhibited memory cell CD40L. Although it has previously been recognized that human endothelial cells can increase T-cell CD40L, this is the first description of the difference in responses of naïve and memory cells and the first demonstration of synergistic effects of endothelial cells and cAMP on CD40L regulation. Consistent with previous reports that CD40L regulation is distinctive, another marker of early activation (CD69) was not similarly regulated. The mechanisms of CD40L regulation were related to calcineurin and calcium/calmodulin dependent kinase IV (CaMKIV) signalling pathways. Endothelial cell costimulation of CD40L was found to be dependent upon calcineurin activity while cAMP actions to increase CD40L were dependent upon CaMKIV. Expression of a dominant negative CaMKIV construct further indicated an important role for CaMKIV in regulation of CD40L and cAMP responses. These data indicate that endothelial cell costimulation can interact with cAMP through calcium signalling pathways to synergistically enhance CD40L expression. Because increased CD40L is associated with atherosclerotic plaque and instability, results are relevant to the pathogenesis of atherosclerosis and myocardial infarction.
目前已认识到CD40配体（CD40L）的表达在血管疾病的发病机制中起作用。由于CD40L水平升高与心肌梗死有关，内皮细胞和环磷酸腺苷（cAMP）对CD40L调节的影响可能具有临床意义。在本研究中，内皮细胞可显著增加初始CD4⁺T细胞上的CD40L，对记忆T细胞的影响较小。此外，添加二丁酰环磷酸腺苷（dbcAMP）可协同增加初始细胞的CD40L，但抑制记忆细胞的CD40L。尽管此前已认识到人类内皮细胞可增加T细胞CD40L，但这是首次描述初始细胞和记忆细胞反应的差异，以及内皮细胞和cAMP对CD40L调节的协同作用。与先前关于CD40L调节具有独特性的报道一致，另一种早期激活标志物（CD69）的调节方式不同。CD40L的调节机制与钙调神经磷酸酶和钙/钙调蛋白依赖性激酶IV（CaMKIV）信号通路有关。发现内皮细胞对CD40L的共刺激依赖于钙调神经磷酸酶的活性，而cAMP增加CD40L的作用依赖于CaMKIV。显性负性CaMKIV构建体的表达进一步表明CaMKIV在CD40L调节和cAMP反应中起重要作用。这些数据表明，内皮细胞共刺激可通过钙信号通路与cAMP相互作用，协同增强CD40L的表达。由于CD40L水平升高与动脉粥样硬化斑块及不稳定性有关，这些结果与动脉粥样硬化和心肌梗死的发病机制相关。
