Department of Anatomy, Cell Biology, and Physiology, School of Veterinary Medicine, University of California, Davis, CA, USA.
Exp Cell Res. 2011 Apr 1;317(6):737-44. doi: 10.1016/j.yexcr.2011.01.007. Epub 2011 Jan 13.
Fluid shear stress regulates gene expression in osteoblasts, in part by activation of the transcription factor NF-κB. We examined whether this process was under the control of purinoceptor activation. MC3T3-E1 osteoblasts under static conditions expressed the NF-κB inhibitory protein IκBα and exhibited cytosolic localization of NF-κB. Under fluid shear stress, IκBα levels decreased, and concomitant nuclear localization of NF-κB was observed. Cells exposed to fluid shear stress in ATP-depleted medium exhibited no significant reduction in IκBα, and NF-κB remained within the cytosol. Similar results were found using oxidized ATP or Brilliant Blue G, P2X(7) receptor antagonists, indicating that the P2X(7) receptor is responsible for fluid shear-stress-induced IκBα degradation and nuclear accumulation of NF-κB. Pharmacologic blockage of the P2Y6 receptor also prevented shear-induced IκBα degradation. These phenomena involved neither ERK1/2 signaling nor autocrine activation by P2X(7)-generated lysophosphatidic acid. Our results suggest that fluid shear stress regulates NF-κB activity through the P2Y(6) and P2X(7) receptor.
流体切应力通过激活转录因子 NF-κB 来调节成骨细胞中的基因表达。我们研究了这一过程是否受到嘌呤能受体激活的控制。在静态条件下，MC3T3-E1 成骨细胞表达 NF-κB 抑制蛋白 IκBα，并表现出 NF-κB 的胞质定位。在流体切应力下，IκBα 水平下降，同时观察到 NF-κB 的核定位。在 ATP 耗尽的培养基中暴露于流体切应力的细胞中，IκBα 没有明显减少，NF-κB 仍留在细胞质中。使用氧化型 ATP 或 Brilliant Blue G（P2X(7) 受体拮抗剂）也得到了类似的结果，表明 P2X(7) 受体负责流体切应力诱导的 IκBα 降解和 NF-κB 的核积累。P2Y6 受体的药理学阻断也阻止了剪切诱导的 IκBα 降解。这些现象既不涉及 ERK1/2 信号，也不涉及 P2X(7) 产生的溶血磷脂酸的自分泌激活。我们的结果表明，流体切应力通过 P2Y(6)和 P2X(7)受体调节 NF-κB 活性。
