title: Inflammation-induced functional connectivity of melanin-concentrating hormone and IL-10.
abstract: Melanin-concentrating hormone (MCH) was identified in mammals as a hypothalamic neuropeptide regulating appetite and energy balance. However, similarly to most of the brain peptides, MCH is also produced in the gastrointestinal system and can act locally as an immunomodulator. We have previously reported high expression of MCH and its receptor MCHR1 in the affected mucosa of patients with inflammatory bowel disease. Furthermore, MCH deficiency in mice attenuated experimental colitis, pointing to MCH as a mediator of intestinal inflammation. In the present study, in order to gain further insights into the underlying mechanisms of such effects of MCH, we treated mice with established experimental colitis due to IL-10 deficiency with a MCHR1 antagonist (DABA-822). While treatment with the same drug was successful in attenuating TNBS-induced colitis in previous studies, it offered no benefit to the IL-10 knockout mouse model, suggesting that perhaps IL-10 is a downstream target of MCH. Indeed, in experiments focusing on monocytes, we found that treatment with MCH inhibited LPS-mediated IL-10 upregulation. Conversely, in the same cells, exogenous IL-10 prevented LPS-induced MCHR1 expression. Taken together, these findings indicate a functional cross-talk between MCH and IL-10 which prevents resolution of inflammation.
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
authors.forename: Dimitrios C
authors.initials: DC
authors.lastname: Ziogas
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
authors.forename: Apostolos K A
authors.initials: AK
authors.lastname: Karagiannis
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Geiger
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Gras-Miralles
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Najarian
authors.affiliation: Cleveland Clinic Foundation Lerner Research Institute, Cleveland, OH 44195, United States.
authors.forename: Ofer
authors.initials: O
authors.lastname: Reizes
authors.affiliation: Penn State College of Medicine, Hershey, PA 17036, United States.
authors.forename: Leo R
authors.initials: LR
authors.lastname: Fitzpatrick
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States. Electronic address: ekokkoto@bidmc.harvard.edu.
authors.forename: Efi
authors.initials: E
authors.lastname: Kokkotou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D003092:Colitis / Q000097:blood* / Q000188:drug therapy / Q000276:immunology; D015870:Gene Expression; D007028:Hypothalamic Hormones / Q000502:physiology*; D016753:Interleukin-10 / Q000097:blood* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008543:Melanins / Q000502:physiology*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010894:Piroxicam / Q000494:pharmacology; D010907:Pituitary Hormones / Q000502:physiology*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000893:Anti-Inflammatory Agents; D007028:Hypothalamic Hormones; D008070:Lipopolysaccharides; C491209:Mchr1 protein, mouse; D008543:Melanins; D010907:Pituitary Hormones; D017481:Receptors, Somatostatin; D016753:Interleukin-10; D010894:Piroxicam; C019463:melanin-concentrating hormone
keywords: Cytokines; IL-10; Intestinal inflammation; Melanin-concentrating hormone; Monocytes; Neuropeptides