Zou Wenying, Meng Xiaojing, Cai Chunqing, Zou Mengchen, Tang Shihao, Chu Xinwei, Wang Xubu, Zou Fei
Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
Cell Physiol Biochem. 2012;30(1):221-37. doi: 10.1159/000339059. Epub 2012 Jun 19.
Neutrophil polarization is a basic activity involved in the innate immune response, and it may be initiated by extracellular Ca(2+) entry, a process primarily mediated through store-operated Ca(2+) entry (SOCE). Yet, the mechanisms by which SOCE participates in cell polarization remain unclear. We hypothesized that Akt- and Src-dependent pathways, traditionally linked to neutrophil polarization, may interact with SOCE in this event. In this study, SKF96365 and 2-APB, inhibitors of SOCE as proved by their inhibition on Mn(2+) influx, were observed to inhibit the formyl-methionyl-leucyl-phenylalanine (fMLP)-induced influx of Ca(2+), the activation of Akt, Src, Rac1, Rac2, and Cdc42, and the polarization of differentiated HL-60 (dHL-60) cells. Downregulation of stromal interaction molecule 1 (STIM1), a Ca(2+) sensor identified to induce SOCE, by siRNA led to decreases in the following indexes: Ca(2+) entry, activation of Akt, Src, Rac2 (rather than Rac1) and Cdc42, and fMLP-induced polarization. This study suggests that SOCE might be the predominant form of Ca(2+) entry involved in the regulation of cell polarization, and it may act through the Akt/Src/Rac pathways, as modeled in dHL-60 cells. It also suggests that STIM1 is a key modulator of cell polarization, potentially serving as a target for the designation of anti-immune deficiency therapies.
中性粒细胞极化是先天免疫反应中涉及的一种基本活动，它可能由细胞外Ca(2+)内流引发，这一过程主要通过钙库操纵的Ca(2+)内流（SOCE）介导。然而，SOCE参与细胞极化的机制仍不清楚。我们推测，传统上与中性粒细胞极化相关的Akt和Src依赖性途径可能在此过程中与SOCE相互作用。在本研究中，观察到SKF96365和2-APB（通过抑制Mn(2+)内流证明为SOCE抑制剂）可抑制甲酰甲硫氨酰亮氨酰苯丙氨酸（fMLP）诱导的Ca(2+)内流、Akt、Src、Rac1、Rac2和Cdc42的激活以及分化的HL-60（dHL-60）细胞的极化。通过小干扰RNA（siRNA）下调基质相互作用分子1（STIM1，一种被确定可诱导SOCE的Ca(2+)传感器），导致以下指标降低：Ca(2+)内流、Akt、Src、Rac2（而非Rac1）和Cdc42的激活以及fMLP诱导的极化。本研究表明，SOCE可能是参与细胞极化调节的Ca(2+)内流的主要形式，并且它可能通过Akt/Src/Rac途径发挥作用，如在dHL-60细胞中所模拟的那样。它还表明STIM1是细胞极化的关键调节因子，可能成为设计抗免疫缺陷疗法的靶点。
