Crucial role of the melanocortin receptor MC1R in experimental colitis

Christian Maaser ^1*, Klaus Kannengiesser ¹, Christoph Specht ¹, Andreas Luegering ¹, Thomas Brzoska ¹, Thomas A. Luger ¹, Wolfram Domschke ¹ and Torsten Kucharzik ¹

¹ University of Muenster, Germany

^* To whom correspondence should be addressed. E-mail: maaser{at}uni-muenster.de.

Accepted 28 February 2006

Abstract

Background and Aims: Alpha-Melanocyte Stimulating Hormone (-MSH) is known to exert anti- inflammatory effects, e.g. in murine DSS-colitis. As the anti-inflammatory functions of -MSH are mediated by the melanocortin1-receptor (MC1R) in an autoregulatory loop, we investigated if a breakdown of the -MSH- MC1R pathway leads to worsening of disease.

Methods: Experimental colitis was induced in mice with a frameshift mutation in the MC1R gene (MC1Re/e), C57BL/6 wildtype mice and MC1Re/e-C57BL/6 bone marrow chimeras. The course of inflammation was monitored by weight loss, histological changes in the colon as well as MPO-activity. Furthermore, MC1R expression was analyzed in intestinal epithelial cells.

Results: While the colon of untreated MC1Re/e appeared normal, the course of DSS-colitis in MC1Re/e mice was dramatically aggravated with a significantly higher weight loss and marked histological changes compared to C57BL/6WT. The inflammation eventually led to death in all MC1Re/e while all C57BL/6WT survived. Similar observations were detected in a transmissible murine colitis model induced by Citrobacter rodentium. Infected MC1Re/e showed a significantly delayed clearance of infection. To determine whether missing hematopoietic cell expressed MC1R is responsible, DSS-colitis was performed with MC1Re/e-C57BL/6 bone marrow chimeras. MC1Re/e mice receiving MC1R+ bone marrow showed a similar course of inflammation as non- transplanted MC1Re/e. Likewise, transplantation of MC1R- bone marrow into C57BL/6WT mice did not lead to any worsening of disease.

Conclusions: This is the first study that demonstrates a functional role of MC1R in intestinal inflammation. Our data suggest a pivotal role of non- hematopoietic cell expressed MC1R in the host's response to pathogenic stimuli.

Keywords: colitis, hormone, inflammation, intestinal, melanocortin

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