Cross-desensitization among CXCR1, CXCR2, and CCR5:: Role of protein kinase C-ε
Cross-desensitization among CXCR1, CXCR2, and CCR5:: Role of protein kinase C-ε
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DOI：
10.4049/jimmunol.174.11.6927
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发表时间：
2005-06-01
影响因子：
4.4
通讯作者：
Richardson, RM
中科院分区：
文献类型：
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作者：
Nasser, MW;Marjoram, RJ;Richardson, RM
IL-8（或CXCL8）趋化因子受体CXCR1和CXCR2激活蛋白激酶C （PKC）介导白细胞功能。为了研究不同PKC异构体在CXCL8受体激活和调节中的作用，我们用CXCL8或CXCL1（黑色素瘤生长刺激活性）处理人单核吞噬细胞，CXCL1是CXCR2特异性的。质膜关联被用作PKC激活的测量。这两种受体都诱导PKC α、- β 1和- β 2与膜的时间依赖性结合，但只有CXCR1激活PKC epsilon。在稳定表达CXCR2的RBL-2H3细胞中，CXCL8也不能激活PKC epsilon。Delta CXCR2是一种抗内化的CXCR2的细胞质尾部缺失突变体，激活PKC epsilon和CXCR1。在rbr - 2h3细胞中表达PKC epsilon抑制剂肽epsilon V1可阻断PKC epsilon易位并抑制受体介导的胞外分泌，但不影响磷酸肌苷水解或细胞内Ca2+动员峰值。epsilon V1还抑制CXCR1-、CCR5-和Delta cxcr2介导的GTPase活性、Ca2+动员和内化的交叉调节信号。来自PKC epsilon缺陷小鼠的腹腔巨噬细胞（PKC epsilon(-/-)）也显示ccr5介导的G蛋白激活和Ca2+动员的交叉脱敏减少。综上所述，结果表明CXCR1和CCR5激活PKC epsilon介导交叉抑制信号。抑制或缺失PKC epsilon会降低受体诱导的胞外分泌和交叉调节信号，但不会降低磷酸肌苷水解或细胞内Ca2+动员峰值，这表明交叉调节是一个不依赖于Ca2+的过程。由于Delta CXCR2而非CXCR2激活PKC epsilon并使CCR5交叉脱敏，因此数据进一步表明，导致新PKC激活的信号持续时间可能调节受体介导的交叉抑制信号。
The IL-8 (or CXCL8) chemokine receptors, CXCR1 and CXCR2, activate protein kinase C (PKC) to mediate leukocyte functions. To investigate the roles of different PKC isoforms in CXCL8 receptor activation and regulation, human mommuclear phagocytes were treated with CXCL8 or CXCL1 (melanoma growth-stimulating activity), which is specific for CXCR2. Plasma membrane association was used as a measure of PKC activation. Both receptors induced time-dependent association of PKC alpha, -beta 1, and -beta 2 to the membrane, but only CXCR1 activated PKC epsilon. CXCL8 also failed to activate PKC epsilon in RBL-2H3 cells stably expressing CXCR2. Delta CXCR2, a cytoplasmic tail deletion mutant of CXCR2 that is resistant to internalization, activated PKC epsilon as well as CXCR1. Expression of the PKC epsilon inhibitor peptide epsilon V1 in RBL-2H3 cells blocked PKC epsilon translocation and inhibited receptor-mediated exocytosis, but not phosphoinositide hydrolysis or peak intracellular Ca2+ mobilization. epsilon V1 also inhibited CXCR1-, CCR5-, and Delta CXCR2-mediated cross-regulatory signals for GTPase activity, Ca2+ mobilization, and internalization. Peritoneal macrophages from PKC epsilon-deficient mice (PKC epsilon(-/-)) also showed decreased CCR5-mediated cross-desensitization of G protein activation and Ca2+ mobilization. Taken together, the results indicate that CXCR1 and CCR5 activate PKC epsilon to mediate cross-inhibitory signals. Inhibition or deletion of PKC epsilon decreases receptor-induced exocytosis and cross-regulatory signals, but not phosphoinositide hydrolysis or peak intracellular Ca2+ mobilization, suggesting that cross-regulation is a Ca2+ -independent process. Because Delta CXCR2, but not CXCR2, activates PKC epsilon and cross-desensitizes CCR5, the data further suggest that signal duration leading to activation of novel PKC may modulate receptor-mediated cross-inhibitory signals.