Ko Jesang, Yun Chi-Young, Lee Ji-Sook, Kim Joo-Hwan, Kim In Sik
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Exp Mol Med. 2007 Apr 30;39(2):129-38. doi: 10.1038/emm.2007.15.
9-cis-Retinoic acid (9CRA) plays an important role in the immune response; this includes cytokine production and cell migration. We have previously demonstrated that 9CRA increases expression of chemokine receptors CCR1 and CCR2 in human monocytes. To better understand how 9CRA induces CCR1 and CCR2 expression, we examined the contribution of signaling proteins in human monocytic THP-1 cells. The mRNA and surface protein up-regulation of CCR1 and CCR2 in 9CRA-stimulated cells were weakly blocked by the pretreatment of SB202190, a p38 MAPK inhibitor, and PD98059, an upstream ERK inhibitor. Activation of p38 MAPK and ERK1/2 was induced in both a time and dose-dependent manner after 9CRA stimulation. Both p38 MAPK and ERK1/2 phosphorylation peaked at 2 h after a 100 nM 9CRA treatment. 9CRA increased calcium influx and chemotactic activity in response to CCR1-dependent chemokines, Lkn-1/CCL15, MIP-1alpha/CCL3, and RANTES/CCL5, and the CCR2-specific chemokine, MCP-1/CCL2. Both SB202190 and PD98059 pretreatment diminished the increased calcium mobilization and chemotactic ability due to 9CRA. SB202190 inhibited the expression and functional activities of CCR1 and CCR2 more effectively than did PD98059. Therefore, our results demonstrate that 9CRA transduces the signal through p38 MAPK and ERK1/2 for CCR1 and CCR2 up-regulation, and may regulate the pro-inflammatory process through the p38 MAPK and ERK-dependent signaling pathways.
9-顺式维甲酸（9CRA）在免疫反应中发挥重要作用；这包括细胞因子的产生和细胞迁移。我们之前已经证明9CRA可增加人单核细胞中趋化因子受体CCR1和CCR2的表达。为了更好地理解9CRA如何诱导CCR1和CCR2的表达，我们研究了信号蛋白在人单核细胞系THP-1细胞中的作用。SB202190（一种p38丝裂原活化蛋白激酶抑制剂）和PD98059（一种上游细胞外信号调节激酶抑制剂）预处理可微弱抑制9CRA刺激细胞中CCR1和CCR2的mRNA及表面蛋白上调。9CRA刺激后，p38丝裂原活化蛋白激酶和细胞外信号调节激酶1/2的激活呈时间和剂量依赖性。在100 nM 9CRA处理后2小时，p38丝裂原活化蛋白激酶和细胞外信号调节激酶1/2的磷酸化均达到峰值。9CRA可增加对CCR1依赖性趋化因子Lkn-1/CCL15、MIP-1α/CCL3和RANTES/CCL5以及CCR2特异性趋化因子MCP-1/CCL2的钙内流和趋化活性。SB202190和PD98059预处理均减少了9CRA引起的钙动员增加和趋化能力。SB202190比PD98059更有效地抑制CCR1和CCR2的表达及功能活性。因此，我们的结果表明9CRA通过p38丝裂原活化蛋白激酶和细胞外信号调节激酶1/2转导信号以上调CCR1和CCR2，并且可能通过p38丝裂原活化蛋白激酶和细胞外信号调节激酶依赖性信号通路调节促炎过程。
