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STAT3 Regulation of Mucosal Inflammation in Pediatric Crohn’s Disease and Murine Colitis

Willson, Tara A.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1330024735

Abstract Details

2012, PhD, University of Cincinnati, Medicine: Cell and Molecular Biology.
Significance: Signal Transducer and Activator of Transcription 3 (STAT3) is crucial for both innate and adaptive mucosal immune responses in human inflammatory bowel disease (IBD) and murine models of colitis. Background: Our lab has reported up-regulation of IL-6:STAT3–dependent biological networks in colonic mucosal biopsies from IBD patients. We identified increased frequency of STAT3 activated lamina propria and epithelial cells that correlated with histologic disease severity and epithelial injury. Recent genome-wide association studies (GWAS) have associated genetic variants in STAT3 with risk for IBD. Goals: Goals that are met in this dissertation are as follows: (1) Determine the functional effect of rs744166 STAT3 IBD risk SNP (STAT3 “A” risk allele) in pediatric Crohn’s disease phenotype, leukocyte recruitment to the gut, peripheral T lymphocyte and granulocyte STAT3 activation, and STAT3 signaling. (2) As no suitable mode for the study of in-vivo epithelial STAT3 specific affects exits, create and characterize an epithelial Stat3 deficient murine model (3) and determine if the loss of STAT3 in the epithelial compartment would promote the development of chronic colitis following acute dextran sodium sulfate (DSS) injury. Results: (1)The STAT3 “A” risk allele is associated with colonic up-regulation of chemokines IL-8, CXCL1, and CXCL3, which promote CXCR2+ neutrophil recruitment to the gut, and the neutrophil activation products, calprotectin (S100A8/S100A9) and S100A12. The frequency of neutrophils expressing CXCR2 was increased, and the frequency of pSTAT3+ or CXCR2+ neutrophils correlated with histologic severity in colonic biopsies from patients carrying the risk allele. Peripheral blood frequency of basal CD4+ lymphocytes and basal and IL-6/IL-6R stimulated granulocytes expressing pSTAT3 was increased in patients carrying the STAT3”A” risk allele. EBV-transformed lymphocytes from patients carrying the STAT3”A” risk allele exhibited increased basal and IL-6 stimulated STAT3 activation. Patient clinical and demographic characteristics did not differ based on STAT3 “A” risk allele genotype although the above-mentioned phenotypic differences seem to define a newly described sub-population of pediatric CD patients. (2-3) In our murine model of intestinal epithelial cell Stat3 deletion (Stat3?IEC) chronic inflammation at day 28 was more severe following 7 days of acute injury with DSS which was not accounted for by a sustained defect in epithelial proliferation or apoptosis as compared to littermate control (Stat3Flx/Flx) mice. Colonic lamina propria frequency of total pSTAT3+ cells was increased and correlated with histologic injury and F480+pSTAT3+ macrophages, and CD3+pSTAT3+ T-lymphocytes were increased in Stat3?IEC mice compared to littermate controls. Colonic expression of Stat3 target genes Reg3ß and Reg3? that mediate epithelial restitution were significantly decreased in Stat3?IEC mice. However colonic expression of Il-17a, IFN?, Cxcl2, Cxcl10, Ccl2, and Ccl4 were significantly increased and Il-17a expression correlated with the increased lamina propria frequency of CD3+pSTAT3+ T-lymphocytes in Stat3?IEC mice. Conclusion: The rs744166 STAT3”A”risk allele is associated with increased cellular STAT3 activation and up-regulation of pathways which promote recruitment of CXCR2+ neutrophils to the gut. The loss of STAT3 activation in the epithelial compartment ultimately leads to a more severe chronic inflammation, reduced epithelial restitution gene expression and expansion of pSTAT3+ lymphocytes and Il-17a expression.
Lee Denson, MD (Committee Chair)
David Hildeman, PhD (Committee Member)
Nelson Horseman, PhD (Committee Member)
Marshall Montrose, PhD (Committee Member)
Yi Zheng, PhD (Committee Member)
243 p.
Cellular Biology
Pediatric Crohn's Disease; Signal Transducer and Activator of Transcription 3; neutrophil recruitment; CXCR2; Dextran Sodium Sulfate (DSS); Interleukin 17A;

Recommended Citations

Citations

  • Willson, T. A. (2012). STAT3 Regulation of Mucosal Inflammation in Pediatric Crohn’s Disease and Murine Colitis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1330024735

    APA Style (7th edition)

  • Willson, Tara. STAT3 Regulation of Mucosal Inflammation in Pediatric Crohn’s Disease and Murine Colitis. 2012. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1330024735.

    MLA Style (8th edition)

  • Willson, Tara. "STAT3 Regulation of Mucosal Inflammation in Pediatric Crohn’s Disease and Murine Colitis." Doctoral dissertation, University of Cincinnati, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1330024735

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.