Date of Graduation

Fall 2016

Degree

Master of Science in Cell and Molecular Biology

Department

Biomedical Sciences

Committee Chair

Tyler Morris

Keywords

inflammatory bowel disease, tumor necrosis factor alpha, tumor necrosis factor alpha converting enzyme, ulcerative colitis, Crohn’s disease

Subject Categories

Medical Molecular Biology

Abstract

Tumor necrosis factor a (TNFα), a potent inflammatory cytokine, has long been established as a major driving force for pathologic inflammation. Currently, anti-TNFα therapies are the standard in Inflammatory Bowel Disease (IBD) management; however, one-third of IBD patients fail to respond to anti-TNFα therapies. Previous data from this lab indicate that TNFα Converting Enzyme (TACE) inhibition does not ameliorate colitis in BALB/C mice. Thus, we hypothesized that TNFα is not a critical component in the BALB/C model of colitis. To test this, acute colitis was induced in BALB/C mice by consumption of 5% dextran sulfate sodium (DSS) in drinking water for 7 days. TACE inhibition was achieved through twice daily intraperitoneal injection of DPC-333 (10 mg/kg; BSM, Inc.) To determine the effects of TACE inhibition during colitis, BALB/C mice received the following experimental treatments: Group 1) H2O + vehicle; Group 2) DSS + vehicle; Group 3) DSS + DPC-333. Although TACE inhibition significantly reduced colon TNFα levels (p = 0.0172), no significant improvement in disease activity was observed (p = 0.74), as determined by clinical scoring of bodyweight loss, rectal bleeding, and diarrhea. Thus, colitis in BALB/C mice does not appear to be TNFα-driven and an alternative pathway must exist. It is possible that BALB/C mice could represent a pre-clinical model of primary non-responders to anti-TNFα therapies. Future studies may use this model to better understand mechanisms of primary non-response in IBD patients.

Copyright

© Carol Elaine Auterson

Open Access

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