ROCKing cytokine secretion balance in human T cells

Balanced regulation of cytokine secretion in T cells is critical for maintenance of immune homeostasis and prevention of autoimmunity. The Rho-associated kinase (ROCK) 2 signaling pathway was previously shown to be involved in controlling of cellular movement and shape. However, recent work from our group and others has demonstrated a new and important role of ROCK2 in regulating cytokine secretion in T cells. We found that ROCK2 promotes pro-inflammatory cytokines such as IL-17 and IL-21, whereas IL-2 and IL-10 secretion are negatively regulated by ROCK2 under Th17-skewing activation. Also, in disease, but not in steady state conditions, ROCK2 contributes to regulation of IFN-γ secretion in T cells from rheumatoid arthritis patients. Thus, ROCK2 signaling is a key pathway in modulation of T-cell mediated immune responses underscoring the therapeutic potential of targeted inhibition of ROCK2 in autoimmunity.     

抑瘤素M受体对慢性自身免疫性荨麻疹发病机制的影响

本研究旨在探讨抑瘤素M受体(OSMR)在慢性自身免疫性荨麻疹(CAU)发病机制中的作用。本研究分别检测30例CAU患者及30名健康受试者的皮肤组织中OSMR、JAK和STAT3的表达,研究显示OSMR、JAK和STAT3在CAU患者皮肤组织中高表达(p<0.05)。转染OSMR-siRNA可显著降低CAU模型小鼠血清炎症因子IL-1、IL-6和IFN-γ水平,而转染JAK/STAT3信号通路激动剂Tyr705则可显著升高炎症因子水平(p<0.05)。转染OSMR-siRNA可显著降低CAU小鼠瘙痒次数、瘙痒时间和嗜酸性粒细胞计数,而转染Tyr705则可显著升高CAU小鼠瘙痒次数、瘙痒时间和嗜酸性粒细胞计数(p<0.05)。转染OSMR-siRNA促进了CAU小鼠上皮细胞的增殖能力,并抑制了细胞凋亡(p<0.05)。而转染Tyr705则抑制了CAU小鼠上皮细胞的增殖能力,并促进了细胞凋亡(p<0.05)。转染OSMR-siRNA下调了上皮细胞中OSMR、JAK和STAT3的表达,而转染Tyr705则上调了OSMR、JAK和STAT3的表达(p<0.05)。总之,本研究表明OSMR基因在CAU患者皮肤组织中高表达。OSMR基因沉默可通过抑制JAK/STAT3信号通路来抑制炎症因子表达及嗜酸性粒细胞数量,促进上皮细胞增殖并抑制细胞凋亡。     

The JAK1/2 inhibitor ruxolitinib delays premature aging phenotypes

Hutchinson–Gilford progeria syndrome (HGPS) is caused by an LMNA mutation that results in the production of the abnormal progerin protein. Children with HGPS display phenotypes of premature aging and have an average lifespan of 13 years. We found earlier that the targeting of the transmembrane protein PLA2R1 overcomes senescence and improves phenotypes in a mouse model of progeria. PLA2R1 is regulating the JAK/STAT signaling, but we do not yet know whether targeting this pathway directly would influence cellular and in vivo progeria phenotypes. Here, we show that JAK1/2 inhibition with ruxolitinib rescues progerin‐induced cell cycle arrest, cellular senescence, and misshapen nuclei in human normal fibroblasts expressing progerin. Moreover, ruxolitinib administration reduces several premature aging phenotypes: bone fractures, bone mineral content, grip strength, and a trend to increase survival in a mouse model of progeria. Thus, we propose that ruxolitinib, an FDA‐approved drug, should be further evaluated as a drug candidate in HGPS therapy.     

Reduced expression of CYLD promotes cell survival and inflammation in gefitinib‐treated NSCLC PC‐9 cells: Targeting CYLD may be beneficial for acquired resistance to gefitinib therapy

The application of tyrosine kinase inhibitors (TKIs) to the epidermal growth factor receptor (EGFR) has been proven to be highly effective for non‐small‐cell lung cancer (NSCLC). However, patients often evolve into acquired resistance. The secondary mutations in EGFR account for nearly half of the acquired resistance. While the remaining 50% of patients exhibit tolerance to EGFR‐TKIs with unclear mechanism(s). Cylindromatosis (CYLD), a deubiquitinase, functions as a tumor suppressor to regulate cell apoptosis, proliferation, and immune response, and so on. The role of CYLD in NSCLC EGFR‐TKI resistance remains elusive. Here, we found CYLD was upregulated in PC‐9 cells, whereas downregulated in PC‐9 acquired gefitinib‐resistant (PC‐9/GR) cells in response to the treatment of gefitinib, which is consistent with the results in the Gene Expression Omnibus database. Overexpression of CYLD promoted a more apoptotic death ratio in PC‐9/GR cells than that in PC‐9 cells. In addition, silencing the expression of CYLD resulted in an increase of the expression level of interleukin‐6, transforming growth factor‐β and tumor necrosis factor‐α, which may contribute to acquired resistance of PC‐9 cells to gefitinib. Taken together, our data in vitro demonstrate that PC‐9/GR cells downregulated CYLD expression, enhanced subsequent CYLD‐dependent antiapoptotic capacity and inflammatory response, which may provide a possible target for acquired gefitinib‐resistant treatment in NSCLC.