Regulation of IL-15-Stimulated TNF-α Production by Rolipram
Regulation of IL-15-Stimulated TNF-α Production by Rolipram
复制标题
Rolipram 对 IL-15 刺激的 TNF-α 产生的调节
作者：
C. Kasyapa;C. L. Stentz;M. Davey;D. Carr
增加细胞内cAMP的药物已被证明可以减少实验性关节炎中的关节炎症，可能是通过降低促炎细胞因子（如TNF-α）的释放。最近的研究表明，在类风湿性关节炎患者的关节中，巨噬细胞释放TNF-α是通过与IL-15刺激的T淋巴细胞相互作用触发的。在这份报告中，我们分析了rolipram，cAMP特异性磷酸二酯酶抑制剂，在这个实验系统中对TNF-α产生的影响。将U937细胞与IL-15刺激的T细胞共培养，但不与对照T细胞共培养，导致TNF-α的释放增加。用咯利普兰或cAMP类似物预处理T细胞可抑制IL-15刺激的细胞增殖、细胞表面分子CD69、ICAM-1和LFA-1的表达以及巨噬细胞释放TNF-α。向T细胞中添加PMA显着增加了细胞表面分子的表达，但对T细胞或共培养物中TNF-α的释放影响很小或没有影响，这表明其他表面分子也必须参与T细胞/巨噬细胞接触介导的TNF-α的产生。加入PMA协同增加IL-15刺激的T细胞的增殖和IL-15刺激的T细胞/巨噬细胞共培养物中TNF-α的分泌。咯利普兰和8-（4-氯苯硫基）-cAMP（CPT-cAMP）阻断了这些增加。蛋白激酶A（PKA）活性的测量和抑制性cAMP类似物（RpCPT-cAMP）的使用证实咯利普兰通过刺激PKA起作用。这些数据表明，PKA激活剂，如咯利普兰，可以通过抑制T细胞活化和表面分子的表达来阻断巨噬细胞分泌TNF-α。
Agents that increase intracellular cAMP have been shown to reduce joint inflammation in experimental arthritis, presumably by lowering the release of proinflammatory cytokines, such as TNF-α. Recent studies suggest that, in joints of patients with rheumatoid arthritis, TNF-α release from macrophages is triggered by their interaction with IL-15-stimulated T lymphocytes. In this report, we analyze the effect of rolipram, a cAMP-specific phosphodiesterase inhibitor, on TNF-α production in this experimental system. Cocultures of U937 cells with IL-15-stimulated T cells, but not control T cells, resulted in increased release of TNF-α. Pretreatment of T cells with rolipram or cAMP analogues inhibited the IL-15-stimulated increases in proliferation, expression of cell surface molecules CD69, ICAM-1, and LFA-1, and release of TNF-α from macrophages. Addition of PMA to T cells dramatically increased the expression of cell surface molecules, but had little or no effect on TNF-α release from either T cells or from cocultures, suggesting that other surface molecules must also be involved in T cell/macrophage contact-mediated production of TNF-α. Addition of PMA synergistically increased the proliferation of IL-15-stimulated T cells and the secretion of TNF-α from IL-15-stimulated T cell/macrophage cocultures. Rolipram and 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) blocked these increases. Measurement of protein kinase A (PKA) activity and the use of inhibitory cAMP analogues (RpCPT-cAMP) confirmed that rolipram worked by stimulating PKA. These data suggest that PKA-activating agents, such as rolipram, can block secretion of TNF-α from macrophages by inhibiting T cell activation and expression of surface molecules.
影响因子：
4.4
作者：
D. Alleva;S. B. Kaser;M. A. Monroy;M. Fenton;D. Beller
通讯作者：
D. Alleva;S. B. Kaser;M. A. Monroy;M. Fenton;D. Beller
影响因子：
15.9
作者：
Oppenheimer-Marks, N;Brezinschek, RI;Lipsky, PE
通讯作者：
Lipsky, PE