Melanin-concentrating hormone as a mediator of intestinal inflammation

Abstract

Melanin-concentrating hormone (MCH) is expressed primarily in the hypothalamus and has a positive impact on feeding behavior and energy balance. Although MCH is expressed in the gastrointestinal tract, its role in this system remains elusive. We demonstrate that, compared to wild type, mice genetically deficient in MCH had substantially reduced local inflammatory responses in a mouse model of experimental colitis induced by intracolonic administration of 2,4,6 trinitrobenzene sulfonic acid (TNBS). Likewise, mice receiving treatments with an anti-MCH antibody, either prophylactically or after the establishment of colitis, developed attenuated TNBS-associated colonic inflammation and survived longer. Consistent with a potential role of MCH in intestinal pathology, we detected increased colonic expression of MCH and its receptor in patients with inflammatory bowel disease. Moreover, we found that human colonic epithelial cells express functional MCH receptors, the activation of which induces IL-8 expression. Taken together, these results clearly implicate MCH in inflammatory processes in the intestine and perhaps elsewhere.experimental colitis ͉ IL-8 ͉ inflammatory bowel disease ͉ neuropeptides ͉ MCH deficient mice M elanin-concentrating hormone (MCH) is a 17-to 19-aa cyclic neuropeptide conserved from fish to human (1) and predominantly localized in the brain (2). Several pharmacological and genetic studies revealed a role for this peptide in the regulation of feeding behavior and energy expenditure toward a positive energy balance (3-5). More recent studies extended the physiological functions of MCH as a broad regulator of cognitive and autonomic aspects related to rewarding behaviors (6, 7). Outside the brain, MCH is localized in the pancreas (8), skin (9), and gastrointestinal tract (10). It has been also found in tissular and circulating immune cells (11)(12)(13)(14). However, the physiological role of MCH in these peripheral tissues has yet to be established.In humans, two G-protein-coupled receptors for MCH have been identified, MCHR1 (also known as SLC1 or GPR24) (15-18) and MCHR2 (19-21), whereas rodents express only MCHR1. In the rodent brain, MCHR1 is expressed in areas important for feeding, learning and motivated behavior, integration of sensory and gustatory inputs, autonomic control, and arousal (22, 23). MCHR1 mRNA is also expressed in the thyroid, kidney, adipose tissue, lung, testes, and tongue (23), whereas functional MCHR1 is also present in lymphocytes (12,14), insulin-producing cell lines (24), and mouse and human pancreatic islets (8).Several neuropeptides that are part of the neuroendocrine system exhibit important immunomodulatory effects and mediate inflammation in various organs, including the intestine (25, 26). There is little evidence to indicate expression of MCHR of either type in the intestine of animals or humans, and the role of MCH in inflammatory responses in the gut or elsewhere has not been evaluated. Based on these considerations and because MCH is also expressed in immune c...

Anti-melanin-concentrating hormone treatment attenuates chronic experimental colitis and fibrosis

“…3C). These findings further support the role of MCH as a modulator of intestinal inflammation, as previously described by our group (23,24).…”

“…Beside the still elusive roles of MCH in gastrointestinal physiology, we have found a significant upregulation of MCH expression in the affected mucosa of patients with IBD, suggesting involvement of this molecule in the pathogenesis of IBD (24). Indeed, MCH-deficient mice appear to be less susceptible to 4,6-trinitrobenzene sulfonic acid (TNBS)-induced acute colitis, pointing to proinflammatory effects of MCH.…”

“…Studies in the rat revealed numerous MCH-containing cells, some of them enterochromaffin cells, in gastric antrum and corpus, duodenum, and colon (19). Our own group has demonstrated MCH and MCHR1 immunoreactivity in the rat myenteric and submucosal plexus (24), whereas others have shown that vagal afferent neurons in both human and rat express MCH and its G protein-coupled seven-transmembrane receptor (MCHR1) (6). Moreover, when tested in an in situ ligated loop experiment, MCH stimulated Na ϩ and K ϩ fluxes in proximal colon; water, as well as Na ϩ and K ϩ fluxes in duodenum; and bicarbonate absorption in the jejunum (20).…”

Transcriptome Changes Associated with Protective Immunity in T and B Cell-Deficient <i>Rag1<sup>-/-</sup> </i> Mutant Zebrafish

“…It is also involved in proliferation and/or survival of hematopoietic progenitors [48]. FGF-2 is expressed in stromal cells, macrophages and leukemic cell lines and is involved in physiological and pathological hematopoiesis [48]. FGF4 is vital for the development of visceral organs and is transcriptionally regulated by lymphoid enhancer factor-1 [49] belonging to subfamily of HMG proteins [50].…”

“…FGF-2 stimulates proliferation, enhances cytokine secretion and prevents apoptosis. It is also involved in proliferation and/or survival of hematopoietic progenitors [48]. FGF-2 is expressed in stromal cells, macrophages and leukemic cell lines and is involved in physiological and pathological hematopoiesis [48].…”