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Activation of an IL-6:STAT3-dependent transcriptome in pediatric-onset inflammatory bowel disease

Carey, Rebecca MD1; Jurickova, Ingrid MD1; Ballard, Edgar MD2; Bonkowski, Erin BS1; Han, Xiaonan PhD1; Xu, Huan MS3; Denson, Lee A. MD1,*

doi: 10.1002/ibd.20342
Original Basic Science Articles

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

1 Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio

2 Department of Pathology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio

3 Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio

* MLC 2010, 3333 Burnet Ave., Cincinnati, OH 45229-3039 (e-mail: lee.denson@cchmc.org)

Received 11 May 2007; Accepted 22 October 2007

Published online 10 December 2007 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: NIH; Grant Numbers: DK02700, DK63956; Grant sponsor: Cincinnati Children's Hospital Research Foundation; Grant sponsor: Crohn's and Colitis Foundation of America; Grant sponsor: Broad Medical Research Program; Grant sponsor: Integrative Morphology Core of the National Institutes of Health (NIH)-supported Children's Hospital Research Foundation Digestive Diseases Research and Development Center; Grant Number: R24 DK64403; Grant sponsor: United States Public Health Service; Grant Number: MO1 RR 08084; Grant sponsor: General Clinical Research Centers Program; Grant sponsor: National Center for Research Resources, NIH.

© Crohn's & Colitis Foundation of America, Inc.
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