Novel therapeutic strategy for the treatment of Inflammatory Bowel Diseases

Persistent Link:
http://hdl.handle.net/10150/194617
Title:
Novel therapeutic strategy for the treatment of Inflammatory Bowel Diseases
Author:
Billerey-Larmonier, Claire
Issue Date:
2010
Publisher:
The University of Arizona.
Rights:
Copyright © 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.
Abstract:
At 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.
Type:
text; Electronic Dissertation
Keywords:
Immunology
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Immunobiology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Kiela, Pawel R.
Committee Chair:
Kiela, Pawel R.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleNovel therapeutic strategy for the treatment of Inflammatory Bowel Diseasesen_US
dc.creatorBillerey-Larmonier, Claireen_US
dc.contributor.authorBillerey-Larmonier, Claireen_US
dc.date.issued2010en_US
dc.publisherThe University of Arizona.en_US
dc.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.en_US
dc.description.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.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectImmunologyen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineImmunobiologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorKiela, Pawel R.en_US
dc.contributor.chairKiela, Pawel R.en_US
dc.contributor.committeememberKatsanis, Emmanuelen_US
dc.contributor.committeememberLybarger, Lonnieen_US
dc.contributor.committeememberRiggs, Michael Wen_US
dc.contributor.committeememberSo, Magdaleneen_US
dc.identifier.proquest10869en_US
dc.identifier.oclc659753782en_US
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