T cell activation induces ER stress and upregulates Inositol Requiring Enzyme 1 alpha (IRE1α), an activator of the unfolded protein response (UPR) pathway. Inhibition of IRE1α RNase activity in activated CD4+ splenocytes from naïve mice, via treatment of the cells with the commercially available drug 4μ8c upon activation, results in the reduction of the secretion of proteins IL-5, IL-4, and IL-13. Prior to this work, it was unknown if 4μ8c could inhibit TH2 cytokines in established TH2 cells, cells that are crucial in promoting disease in severe asthma. Treatment of a mouse T helper (TH)2 cell line and differentiated human TH2 cells with 4μ8c resulted in inhibition of IL-5, but not IL-4, as measured by ELISA. The reduced cytokine expression was not due to differences in mRNA stability or mRNA levels; it appears to be due to a defect in secretion, as the cells produce cytokines IL-5 as measured by flow cytometry and western blot. These data suggest that the inhibition of IL-5 was due to post-translational processes. IL-5 promotes chronic, inflammatory asthma, and 4μ8c blocks its expression in T cells in vitro. Future studies will determine if 4μ8c treatment can ameliorate the effects of the cytokine IL-5 in a disease model.

中文翻译：

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用IRE1α抑制剂4μ8c处理已建立的TH2细胞可阻断IL-5分泌，但不能阻断IL-4分泌

T细胞活化可诱导内质网应激，并上调需要酶1α（IRE1α）的肌醇，这是未折叠蛋白反应（UPR）途径的激活剂。幼稚小鼠的活化CD4 +脾细胞中IRE1αRNase活性的抑制，通过在活化后用市售药物4μ8c处理细胞，导致IL-5，IL-4和IL-13蛋白质的分泌减少。在这项工作之前，尚不清楚4μ8c是否能抑制已建立的TH2细胞中的TH2细胞因子，TH2细胞是在严重哮喘中促进疾病的关键细胞。用ELISA检测，用4μ8c处理小鼠T辅助（TH）2细胞系和分化的人TH2细胞可抑制IL-5，但不能抑制IL-4。细胞因子表达的降低不是由于mRNA稳定性或mRNA水平的差异所致。它似乎是由于分泌缺陷造成的，因为通过流式细胞仪和蛋白质印迹法检测到细胞会产生细胞因子IL-5。这些数据表明IL-5的抑制是由于翻译后过程。IL-5会促进慢性炎症性哮喘，并且4μ8c在体外会阻止其在T细胞中的表达。未来的研究将确定4μ8c治疗是否可以改善细胞因子IL-5在疾病模型中的作用。