title: Anti-melanin-concentrating hormone treatment attenuates chronic experimental colitis and fibrosis.
abstract: Fibrosis represents a major complication of several chronic diseases, including inflammatory bowel disease (IBD). Treatment of IBD remains a clinical challenge despite several recent therapeutic advances. Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide shown to regulate appetite and energy balance. However, accumulating evidence suggests that MCH has additional biological effects, including modulation of inflammation. In the present study, we examined the efficacy of an MCH-blocking antibody in treating established, dextran sodium sulfate-induced experimental colitis. Histological and molecular analysis of mouse tissues revealed that mice receiving anti-MCH had accelerated mucosal restitution and lower colonic expression of several proinflammatory cytokines, as well as fibrogenic genes, including COL1A1. In parallel, they spared collagen deposits seen in the untreated mice, suggesting attenuated fibrosis. These findings raised the possibility of perhaps direct effects of MCH on myofibroblasts. Indeed, in biopsies from patients with IBD, we demonstrate expression of the MCH receptor MCHR1 in α-smooth muscle actin(+) subepithelial cells. CCD-18Co cells, a primary human colonic myofibroblast cell line, were also positive for MCHR1. In these cells, MCH acted as a profibrotic modulator by potentiating the effects of IGF-1 and TGF-β on proliferation and collagen production. Thus, by virtue of combined anti-inflammatory and anti-fibrotic effects, blocking MCH might represent a compelling approach for treating IBD.
authors.affiliation: Beth Israel Deaconess Medical Center, Dana 501, 330 Brookline Ave., Boston, MA 02215, USA.
authors.forename: Dimitrios C
authors.initials: DC
authors.lastname: Ziogas
authors.forename: Beatriz
authors.initials: B
authors.lastname: Gras-Miralles
authors.forename: Sarah
authors.initials: S
authors.lastname: Mustafa
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Geiger
authors.forename: Robert M
authors.initials: RM
authors.lastname: Najarian
authors.forename: Jutta M
authors.initials: JM
authors.lastname: Nagel
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Flier
authors.forename: Yury
authors.initials: Y
authors.lastname: Popov
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Tseng
authors.forename: Efi
authors.initials: E
authors.lastname: Kokkotou
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D049109:Cell Proliferation; D003092:Colitis / Q000188:drug therapy* / Q000473:pathology; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D003108:Colonic Diseases / Q000188:drug therapy* / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy; D007028:Hypothalamic Hormones / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D008543:Melanins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism; D010907:Pituitary Hormones / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D017481:Receptors, Somatostatin / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015854:Up-Regulation / Q000502:physiology; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000199:Actins; D015415:Biomarkers; D007028:Hypothalamic Hormones; C491209:Mchr1 protein, mouse; D008543:Melanins; D010907:Pituitary Hormones; D017481:Receptors, Somatostatin; D016212:Transforming Growth Factor beta; C544013:alpha-smooth muscle actin, mouse; C019463:melanin-concentrating hormone; D007334:Insulin-Like Growth Factor I; D003094:Collagen
keywords: Crohn's disease; chronic dextran sodium sulfate colitis; experimental colitis; inflammatory bowel disease; intestinal fibrosis; melanin-concentrating hormone; myofibroblasts; ulcerative colitis
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