急性期川崎病信号转导和转录激活因子3的表达及意义

目的:探讨急性期川崎病IL-6介导信号转导和转录激活因子3的表达及意义。方法:急性期川崎病(KD)患儿64例,感染发热患儿18例,正常同年龄对照42例。采用Western blot检测外周血单个核细胞(PBMCs)IL-6刺激前后总蛋白,核蛋白STAT3,pSTAT3的表达水平。荧光定量PCR检测PBMCs IL-6刺激前后及IL-6R抗体阻断后STAT3 mRNA的表达水平。结果:急性期KD患儿PBMCs用IL-6刺激前、后总蛋白STAT3,pSTAT3表达水平高于正常儿童;核蛋白则为IL-6刺激前KD患儿STAT3,pSTAT3表达与正常儿童无明显差异,IL-6刺激后KD患儿STAT3,pSTAT3表达明显高于正常儿童。IL-6刺激前、后KD患儿STAT3 mRNA水平(1.15±0.19,1.74±0.59)均高于感染发热患儿(1.07±0.21,1.45±0.32)及正常儿童(0.56±0.37,1.03±0.51);KD冠脉损伤组(1.19±0.21,1.81±0.47)STAT3 mRNA高于冠脉未损伤组(1.13±0.29,1.73±0.48)。经IL-6R抗体阻断后,KD患儿STAT3 mRNA水平低于IL-6刺激前、后KD患儿及感染发热组(0.99±0.15)。结论:急性期KD患儿体内存在刺激STAT3表达和活化的因素,体外IL-6刺激能增强STAT3的表达和活化并进入细胞核;阻断实验提示IL-6在KD患儿STAT3过度表达、活化中起主导作用,本研究为用IL-6R阻断剂治疗川崎病提供了实验证据。     

An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4(+) T cells

The IL-2/IL-2R signaling pathway has an important role in autoimmunity. Several genes identified in genome-wide association (GWA) studies encode proteins in the IL-2/IL-2R signaling cascade that are associated with autoimmune diseases. One of these, PTPN2, encodes a protein tyrosine phosphatase that is highly expressed in T cells and regulates cytokine signaling. An intronic risk allele in PTPN2, rs1893217(C), correlated with decreased IL-2R signaling in CD4(+) T cells as measured by phosphorylation of STAT5 (phosphorylated STAT5 (pSTAT5)). We modeled an additive single nucleotide polymorphism (SNP) genotype, in which each copy of the risk allele conferred a decrease in IL-2R signaling (P=4.4 × 10(-8)). Decreased pSTAT5 impacted IL-2Rβ chain signaling resulting in reduced FOXP3 expression in activated cells. This phenotype was not due to overt differences in expression of the IL-2R, molecules in the IL-2R signaling cascade or defects in STAT5. However, the rs1893217(C) risk variant did correlate with decreased PTPN2 expression in CD4(+)CD45RO T cells (P=0.0002). Thus, the PTPN2rs1893217(C) risk allele associated with reduced pSTAT5 in response to IL-2 and reduced PTPN2 expression. Together, these data suggest that decreased expression of PTPN2 may indirectly modulate IL-2 responsiveness. These findings, identified through genotype/phenotype relationships, may lead to identification of novel mechanisms underlying dysregulation of cytokine signaling in autoimmunity.     

磷酸化STAT3在非小细胞肺癌组织中的表达及其临床意义

目的:探讨磷酸化信号转导与转录激活因子3(pSTAT3)在非小细胞肺癌(NSCLC)中的表达及其与NSCLC各临床病理因素的关系。方法:采用免疫组织化学染色法检测59例NSCLC及其癌旁组织中pSTAT3的表达。结果:(1)NSCLC组织中,pSTAT3的表达明显高于癌旁组织(P<0.01);(2)pSTAT3的阳性表达与肿瘤组织的大小及NSCLC患者的吸烟状况有关,与性别、年龄、淋巴结转移、临床分期及组织分化程度无关。pSTAT3在腺癌中的阳性表达率较鳞癌高,但无统计学意义。结论:pSTAT3可能在肺癌的发生发展及指导靶向治疗中发挥重要作用。     

Expression of Mcl-1 in mantle cell lymphoma is associated with high-grade morphology,a high proliferative state,and p53 overexpression

Mantle cell lymphoma (MCL) is a distinct type of B-cell non-Hodgkin's lymphoma characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. Defects in apoptosis may contribute to pathogenesis. This study evaluated the expression of the anti-apoptotic protein Mcl-1 in two MCL cell lines and five frozen MCL tumours (four small-cell, one blastoid/large-cell) using western blot analysis. Mcl-1 expression was also assessed in 36 formalin-fixed, paraffin wax-embedded MCL tumours (24 small-cell, 12 blastoid/large-cell) by immunohistochemistry. Western blot analysis revealed the expected 37 kD protein product in both MCL cell lines and in five frozen tumours, with the blastoid case having the highest expression level. Using a cut-off of >10% immunolabelled cells for Mcl-1, it was found that 12 of 36 MCL tumours were positive. Mcl-1-positive tumours had a higher frequency of blastoid/large-cell morphology (8/12 versus 4/24, p = 0.009), p53 overexpression (3/10 versus 1/23, p = 0.04), and higher Ki67 immuno-labelling (p = 0.002). It is concluded that expression of Mcl-1 in MCL is heterogeneous. A relatively high level of Mcl-1 expression correlates with high-grade morphology, a high proliferative state, and p53 overexpression.