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

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http://www3.interscience.wiley.com/cgi-bin/abstract/117861047/ABSTRACT?CRETRY=1 & SRETRY=0

Original Article

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

Carey, MD 1, Ingrid Jurickova, MD 1, Edgar Ballard, MD 2, Bonkowski, BS 1, Xiaonan Han, PhD 1, Huan Xu, MS 3, Lee A. Denson, MD 1 *

1Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio2Department of Pathology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio3Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio

email: Lee A. Denson (lee.denson@...)

*Correspondence to Lee A. Denson, MLC 2010, 3333 Burnet Ave., Cincinnati, OH 45229-3039

Funded by: NIH; Grant Number: DK02700, DK63956 Cincinnati Children's Hospital Research Foundation Crohn's and Colitis Foundation of America Broad Medical Research Program 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 United States Public Health Service; Grant Number: MO1 RR 08084 General Clinical Research Centers Program National Center for Research Resources, NIH

Keywords

interleukin-6 • Crohn's disease • ulcerative colitis • chemokines • microarray

Abstract

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.

(Inflamm Bowel Dis, Volume 14, Issue 4 , Pages 446 - 457, 2007)

Received: 11 May 2007; Accepted: 22 October 2007

Digital Object Identifier (DOI)10.1002/ibd.20342