Chemokine production by G protein-coupled receptor activation in a human mast cell line: Roles of extracellular signal-regulated kinase and NFAT
Chemokine production by G protein-coupled receptor activation in a human mast cell line: Roles of extracellular signal-regulated kinase and NFAT
复制标题
DOI：
10.4049/jimmunol.165.12.7215
复制
发表时间：
2000-12-15
影响因子：
4.4
通讯作者：
Patel, DD
中科院分区：
文献类型：
--
作者：
Ali, H;Ahamed, J;Patel, DD
化学引诱剂被认为是细菌感染部位产生的第一个介质。我们假设通过G蛋白偶联的化学引诱物受体的信号传导可能刺激细胞因子的产生。为了验证这一假设，将正常情况下以低水平表达补体成分C3 a和C5 a的受体的人肥大细胞系（HMC-1）稳定转染以表达生理水平的fMLP受体。我们发现，fMLP而不是C3 a或C5 a诱导巨噬细胞炎性蛋白（MIP）-1 β（CCL 4）和单核细胞趋化蛋白-1（CCL 2）mRNA和蛋白。虽然fMLP刺激持续的Ca 2+动员和细胞外信号调节激酶（ERK）的磷酸化，这些反应C3 a或C5 a是短暂的。然而，HMC-1细胞中C3 a受体的瞬时表达使细胞对C3 a产生持续的Ca 2+动员和MIP-1 β产生反应。百日咳毒素、PD 98059和环孢菌素A分别抑制G（i）α活化、丝裂原活化蛋白激酶激酶介导的ERK磷酸化和钙调神经磷酸酶介导的NFAT活化，从而阻断fMLP诱导的趋化因子的产生。这些数据表明，趋化因子受体诱导HMC-1细胞中的趋化因子产生的选择性取决于受体表达水平，其信号传导时间的长度，以及多种信号传导途径的协同相互作用，包括细胞外信号调节激酶磷酸化，持续的Ca 2+动员和NFAT活化。
Chemoattractants are thought to be the first mediators generated at sites of bacterial infection. We hypothesized that signaling through G protein-coupled chemoattractant receptors may stimulate cytokine production. To test this hypothesis, a human mast cell line (HMC-1) that normally expresses receptors for complement components C3a and C5a at low levels was stably transfected to express physiologic levels of fMLP receptors, We found that fMLP, but not C3a or C5a, induced macrophage inflammatory protein (MIP)-1 beta (CCL4) and monocyte chemoattractant protein-1 (CCL2) mRNA and protein. Although fMLP stimulated both sustained Ca2+ mobilization and phosphorylation of extracellular signal-regulated kinase (ERK), these responses to C3a or C5a were transient. However, transient expression of C3a receptors in HMC-1 cells rendered the cells responsive to C3a for sustained Ca2+ mobilization and MIP-1 beta production. The fMLP-induced chemokine production was blocked by pertussis toxin, PD98059, and cyclosporin A, which respectively inhibit G(i)alpha activation, mitgen-activated protein kinase kinase-mediated ERK phosphorylation, and calcineurin-mediated activation of NFAT, Furthermore, fMLP, but not C5a, stimulated NFAT activation in HMC-1 cells. These data indicate that chemoattractant receptors induce chemokine production in HMC-1 cells with a selectivity that depends on the level of receptor expression, the length of their signaling time, and the synergistic interaction of multiple signaling pathways, including extracellular signal-regulated kinase phosphorylation, sustained Ca2+ mobilization and NFAT activation.