STAT3 基因型变异与细胞 STAT3 激活和儿童克罗恩病结肠白细胞募集。
STAT3 genotypic variation and cellular STAT3 activation and colon leukocyte recruitment in pediatric Crohn disease.
机构信息
Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
出版信息
J Pediatr Gastroenterol Nutr. 2012 Jul;55(1):32-43. doi: 10.1097/MPG.0b013e318246be78.
OBJECTIVES
Genotypic variation in signal transducer and activator of transcription 3 (STAT3) increases risk for inflammatory bowel disease (IBD), and STAT3-dependent inflammatory networks are induced in the colon in these patients. We hypothesized that STAT3 "A" risk allele carriage would be associated with increased cellular STAT3 activation and colon leukocyte recruitment.
METHODS
Colonic expression of genes regulating STAT3 signaling and leukocyte recruitment and function was measured in pediatric patients with Crohn disease (CD) stratified by STAT3 genotype. The frequency of colonic pSTAT3* and CXCR2* neutrophils was determined using immunohistochemistry. STAT3 tyrosine phosphorylation (pSTAT3) was measured in circulating leukocytes by flow cytometry, and mechanisms regulating STAT3 activation were tested in IBD Epstein-Barr virus (EBV)-transformed lymphocytes (EBL).
RESULTS
Colonic expression of interleukin 6 (IL-6), the STAT3 target gene SOCS3, the neutrophil chemoattractants IL-8, CXCL1, and CXCL3, and the neutrophil products S100A8, S100A9, and S100A12 were increased in patients carrying the STAT3 "A" risk allele. The frequency of neutrophils expressing the cognate receptor for IL-8, CXCR2, was increased in colonic biopsies from patients carrying the risk allele, and the frequency of pSTAT3* or CXCR2* neutrophils correlated with histologic severity. The frequency of CD4 lymphocytes and granulocytes expressing pSTAT3 was increased in patients carrying the STAT3 "A" risk allele. EBLs from patients carrying the STAT3 "A" risk allele exhibited increased basal and IL-6-stimulated STAT3 tyrosine phosphorylation, increased transcription of STAT3 and SOCS3 after IL-6 stimulation, and increased membrane localization of the IL-6 receptor, GP130, and Janus-associated kinase 2.
CONCLUSIONS
The STAT3 "A" risk allele is associated with increased cellular STAT3 activation and upregulation of pathways that promote recruitment of CXCR2* neutrophils to the gut.
目的
信号转导子和转录激活子 3（STAT3）的基因型变异增加了炎症性肠病（IBD）的风险，并且这些患者的结肠中诱导了依赖 STAT3 的炎症网络。我们假设 STAT3“A”风险等位基因的携带与细胞 STAT3 激活和结肠白细胞募集的增加有关。
方法
根据 STAT3 基因型对患有克罗恩病（CD）的儿科患者进行分层，测量调节 STAT3 信号和白细胞募集和功能的基因在结肠中的表达。使用免疫组织化学测定 CXCR2中性粒细胞的结肠 pSTAT3和 CXCR2*。通过流式细胞术测量循环白细胞中的 STAT3 酪氨酸磷酸化（pSTAT3），并在 IBD Epstein-Barr 病毒（EBV）转化的淋巴细胞（EBL）中测试调节 STAT3 激活的机制。
结果
携带 STAT3“A”风险等位基因的患者中，白细胞介素 6（IL-6）、STAT3 靶基因 SOCS3、中性粒细胞趋化因子 IL-8、CXCL1、CXCL3 和中性粒细胞产物 S100A8、S100A9 和 S100A12 的结肠表达增加。携带风险等位基因的患者结肠活检中表达 IL-8 同源受体 CXCR2 的中性粒细胞频率增加，pSTAT3或 CXCR2中性粒细胞的频率与组织学严重程度相关。携带 STAT3“A”风险等位基因的患者中 CD4 淋巴细胞和粒细胞表达 pSTAT3 的频率增加。携带 STAT3“A”风险等位基因的 EBL 表现出基础和 IL-6 刺激的 STAT3 酪氨酸磷酸化增加、IL-6 刺激后 STAT3 和 SOCS3 的转录增加以及 IL-6 受体、GP130 和 Janus 相关激酶 2 的膜定位增加。
结论
STAT3“A”风险等位基因与细胞 STAT3 激活增加以及促进 CXCR2*中性粒细胞募集到肠道的途径上调有关。
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