Department of Pharmacology and Anesthesiology, University of Padua, Largo E. Meneghetti 2, Padua, Italy.
Cell Stress Chaperones. 2011 May;16(3):329-38. doi: 10.1007/s12192-010-0245-3. Epub 2010 Dec 1.
Grp94 is the main endoplasmic reticulum-resident heat shock protein (HSP) that besides chaperoning native proteins, displays important modulatory effects on both the innate and adaptive immune response. Since the knowledge of a direct influence of Grp94 on the humoral response is lacking, in this work we tested the effect of Grp94 on Ig secretion from peripheral blood mononuclear cells (PBMCs) of five normal volunteers. The concentration of Ig secreted in the medium after incubation of 15 days was found increased in a dose-dependent manner in the presence of Grp94, used at the final concentrations of 10 and 100 ng/ml. However, by measuring the Ig secretion at different incubation times, it was apparent that maximal percent stimulation by Grp94 occurred at 7 days, decreasing thereafter. In addition, the pattern of Ig secretion in time significantly differed in the presence of Grp94 with respect to that of control PBMCs. Grp94 also stimulated in a dose-dependent manner the PBMC proliferation, an effect that preceded the Ig secretion and was accompanied by morphological changes of cells similar to those induced by the pokeweed mitogen. Effects of Grp94 on PBMCs were mediated by an intense activation of the MEK-ERK1/2 pathway and by an increased expression of HSP90. Results indicate that Grp94 can activate the humoral response by a cytokine-like, cell-mediated mechanism that leads to an accelerated process of B cell maturation and differentiation.
Grp94 是主要的内质网驻留热休克蛋白（HSP），除了伴侣天然蛋白外，还对先天和适应性免疫反应具有重要的调节作用。由于缺乏 Grp94 对体液反应的直接影响的知识，在这项工作中，我们测试了 Grp94 对来自五名正常志愿者外周血单核细胞（PBMC）的 Ig 分泌的影响。在存在 Grp94 的情况下，孵育 15 天后在培养基中分泌的 Ig 浓度以剂量依赖性方式增加，Grp94 的终浓度为 10 和 100ng/ml。然而，通过测量不同孵育时间的 Ig 分泌，显然 Grp94 的最大刺激百分比发生在第 7 天，此后减少。此外，在存在 Grp94 的情况下，Ig 分泌的时间模式与对照 PBMC 的时间模式显著不同。Grp94 还以剂量依赖性方式刺激 PBMC 增殖，这种作用先于 Ig 分泌，并伴有类似于植物血凝素诱导的细胞形态变化。Grp94 对 PBMC 的作用是通过强烈激活 MEK-ERK1/2 途径和 HSP90 的表达增加来介导的。结果表明，Grp94 可以通过细胞因子样的细胞介导机制激活体液反应，从而加速 B 细胞成熟和分化的过程。
