Chemokine production by G protein-coupled receptor activation in a human mast cell line: Roles of extracellular signal-regulated kinase and NFAT

被引:56
作者
Ali, H
Ahamed, J
Hernandez-Munain, C
Baron, JL
Krangel, MS
Patel, DD
机构
[1] Univ Penn, Sch Dent Med, Dept Pathol, Philadelphia, PA 19104 USA
[2] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[3] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA
关键词
D O I
10.4049/jimmunol.165.12.7215
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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页码:7215 / 7223
页数:9
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