Carey Rebecca, Jurickova Ingrid, Ballard Edgar, Bonkowski Erin, Han Xiaonan, Xu Huan, Denson Lee A
Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Inflamm Bowel Dis. 2008 Apr;14(4):446-57. doi: 10.1002/ibd.20342.
While activation of the IL-6-dependent transcription factor signal transducer and activator of transcription 3 (STAT3) has been implicated in the pathogenesis of inflammatory bowel disease (IBD), a direct effect on mucosal gene expression and inflammation has not been shown. We hypothesized that a proinflammatory IL-6:STAT3-dependent biological network would be up regulated in pediatric-onset IBD patients, and would be associated with the severity of mucosal inflammation.
Patients with pediatric-onset IBD were enrolled at diagnosis and during therapy. Serum cytokine analysis was performed using Bioplex. STAT3 phosphorylation (pSTAT3) in peripheral blood leukocytes (PBLs) was assessed by flow cytometry. Immunohistochemistry of colonic mucosa was used to localize pSTAT3 and STAT3 target genes. Microarray analysis was used to determine RNA expression profiles from colon biopsies.
Circulating IL-6 was upregulated in active IBD patients at diagnosis and during therapy. STAT3 activation was increased in PB granulocytes, IL-6-stimulated CD3(+)/CD4(+) lymphocytes, and affected colon biopsies of IBD patients. The frequency of pSTAT3+ PB granulocytes and colon epithelial and lamina propria cells was highly correlated with the degree of mucosal inflammation. Microarray and Ingenuity Systems bioinformatics analysis identified IL-6:STAT3-dependent biological networks upregulated in IBD patients which control leukocyte recruitment, HLA expression, angiogenesis, and tissue remodeling.
A proinflammatory IL6:STAT3 biologic network is upregulated in active pediatric IBD patients at diagnosis and during therapy. Specific targeting of this network may be effective in reducing mucosal inflammation.
虽然白细胞介素-6（IL-6）依赖的转录因子信号转导和转录激活因子3（STAT3）的激活与炎症性肠病（IBD）的发病机制有关，但尚未显示其对黏膜基因表达和炎症有直接影响。我们假设，促炎的IL-6：STAT3依赖生物网络在儿童期发病的IBD患者中会上调，并与黏膜炎症的严重程度相关。
儿童期发病的IBD患者在诊断时和治疗期间入组。使用Bioplex进行血清细胞因子分析。通过流式细胞术评估外周血白细胞（PBL）中的STAT3磷酸化（pSTAT3）。结肠黏膜免疫组织化学用于定位pSTAT3和STAT3靶基因。微阵列分析用于确定结肠活检组织的RNA表达谱。
在诊断时和治疗期间，活动期IBD患者的循环IL-6上调。IBD患者的PB粒细胞、IL-6刺激的CD3(+)/CD4(+)淋巴细胞以及受影响的结肠活检组织中STAT3激活增加。pSTAT3+ PB粒细胞以及结肠上皮和固有层细胞的频率与黏膜炎症程度高度相关。微阵列和Ingenuity Systems生物信息学分析确定，IBD患者中IL-6：STAT3依赖的生物网络上调，该网络控制白细胞募集、HLA表达、血管生成和组织重塑。
在诊断时和治疗期间，活动期儿童IBD患者中促炎的IL-6：STAT3生物网络上调。对该网络进行特异性靶向治疗可能有效减轻黏膜炎症。
