Novel therapeutic strategy for the treatment of Inflammatory Bowel Diseases
AdvisorKiela, Pawel R.
Committee ChairKiela, Pawel R.
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PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractAt least 1.4 million of Americans suffer from Inflammatory Bowel Diseases (IBD). IBD (Crohn’s disease and ulcerative colitis) is a spontaneously relapsing, immunologically mediated disorder of the gastrointestinal tract. Complete medical cure remains a challenge and the probability of relapse is over 70%. Curcumin has been shown to have a protective role in mouse models of inflammatory bowel diseases (IBD) and to reduce the relapse rate in human ulcerative colitis (UC), thus making it a potentially viable supportive treatment option. The objective of this research project was to provide a preclinical evaluation of curcumin’s efficacy in relevant models of human IBD, and to investigate the molecular mechanisms of its protective mechanism of action. (1) We investigated the effect of dietary curcumin in trinitrobenzene sulfonic acid (TNBS)-induced colitis in SJL/J mice (Th-1/Th-17 response) and in BALB/c mice (Th-1/Th-2 response). We demonstrated that the efficacy of dietary curcumin varies in the two strains. Although the exact mechanism underlying these differences remains unclear, our observations suggest that the therapeutic value of dietary curcumin may vary depending on the nature of immune dysregulation. (2) We further confirmed those findings and we investigated the effects of curcumin on the development of colitis, immune activation, and in vivo NF-κB activity in germ-free IL-10^(–/–) colonized with specific pathogen-free microflora. In this model resembling CD, we demonstrated that IL-10 and curcumin act synergistically to downregulate inflammation. (3) Neutrophil aberrant accumulation at the intestinal mucosa is a characteristic hallmark of inflammatory conditions such as ulcerative colitis. Neutrophil transepithelial migration leads to an impaired epithelial barrier function, perpetuation of inflammation and tissue destruction. Therefore, we investigated the effect of curcumin on neutrophil polarization and motility. Our results indicated that curcumin interferes with colonic inflammation partly through chemokine expression inhibition and neutrophil chemotaxis and chemokinesis inhibition. We also demonstrated that curcumin significantly reduced epithelial tissue injury generated by neutrophil transepithelial migration and protease release. Those findings significantly add to our understanding of the mechanism by which curcumin affects the innate and adaptive immune response in IBD and may help develop innovative therapeutic strategy for IBD.