Scientific Abstract
Proposal No. IBD-0038
Principal Investigator: Torsten Kucharzik, M.D.
Applicant Organization: University of Münster (Germany)
Project Title: Role of alpha-MSH and related tripeptides as potential anti-inflammatory agents during inflammatory bowel disease
Period of Award: January 1, 2003 – December 31, 2004
The pathogenesis of chronic inflammatory bowel disease (IBD) is largely unknown. Therefore, the treatment of chronic active IBD is mainly based on broad acting anti-inflammatory agents, such as glucocorticoids or azathioprine. Unfortunately, these drugs have a variety of side effects and failure of treatment is observed in a high percentage of IBD patients. The development of new drugs is therefore mandatory.
Alpha-melanocyte-stimulating hormone (α-MSH) is an endogenous anti-inflammatory peptide derived from pro-opiomelanocortin (POMC). A variety of cells produce constitutively or under appropriate stimulation greater amounts of α-MSH. It has been shown that α-MSH exerts anti-inflammatory effects in vitro and in vivo that are mainly mediated via inhibition of TNF-α and NF-κB-mediated transcription. Recently, it has been shown that the anti-inflammatory properties reside in the C-terminal part of α-MSH, which consists of three amino acids (a-MSH, KPV). The influence of α-MSH is mediated mainly through binding to melanocortin-receptors. MC1R has been shown to have the greatest affinity for α-MSH. Anti-inflammatory properties of α-MSH and KPV have been demonstrated in vitro and in vivo, including human subjects.
Our hypothesis is that a-MSH and its related tripeptide (α-MSH, KPV) have anti-inflammatory properties during inflammatory bowel disease and that the mechanism is based in part through action of MC1R on intestinal epithelial cells.
The aim of our study is therefore to evaluate the anti-inflammatory properties of α-MSH and its related tripeptide in different animal models of IBD. As the epithelium plays a major role during the initiation and perpetuation of IBD, we want to elucidate the effect of these peptides in colitis models that involve the intestinal epithelium, such as the DSS colitis and the Citrobacter rodentium induced colitis. In vitro assays have shown that α-MSH may also involve different cell types such as monocytes, dendritic cells, T- and B-cells. We therefore will include IL-10 deficient mice in our study as a colitis model that predominantly involves T-cells and macrophages.
To further characterize mechanisms of α-MSH action in intestinal epithelial cells, the goal of our project is to determine expression of α-MSH and MC-receptors on intestinal epithelial cell lines as well as in tissue from patients with IBD. Further studies will involve properties of α-MSH and the related tripeptide to inhibit IL-8 and NFκB mediated transcription. We will also elucidate the relevance of MC1R during the anti-inflammatory action of α-MSH as well as KPV in vitro and in vivo.
From our results, we hope to receive an answer of whether α-MSH and, in particular, the related tripeptide KPV are useful agents that can be used as anti-inflammatory agents during inflammatory bowel disease. Studies of the involvement of MC1R will give information on whether this receptor may serve as an important cellular target for the development of new drugs that can be used to treat patients with chronic inflammatory bowel disease.