Ectopic expression of OX1R in ulcerative colitis mediates anti-inflammatory effect of orexin-A

Orexins (orexin-A and orexin-B) are hypothalamic peptides that are produced by the same precursor and are involved in sleep/wake control, which is mediated by two G protein-coupled receptor subtypes, OX1R and OX2R. Ulcerative colitis (UC) is an inflammatory bowel disease, (IBD) which is characterize...

Full description

Saved in:

Bibliographic Details
Published in:	Biochimica et biophysica acta. Molecular basis of disease Vol. 1864; no. 11; pp. 3618 - 3628
Main Authors:	Messal, N., Fernandez, N., Dayot, S., Gratio, V., Nicole, P., Prochasson, C., Chantret, I., LeGuilloux, G., Jarry, A., Couvelard, A., Tréton, X., Voisin, T., Ogier-Denis, E., Couvineau, A.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-11-2018 Elsevier
Subjects:	Adult Animals Cancer Cell Line Colitis, Ulcerative - chemically induced Colitis, Ulcerative - drug therapy Colitis, Ulcerative - immunology Colitis, Ulcerative - pathology Cytokines - immunology Cytokines - metabolism Dextran Sulfate - toxicity Disease Models, Animal Down-Regulation Ectopic Gene Expression Epithelial Cells - drug effects Epithelial Cells - immunology Epithelial Cells - metabolism Epithelial Cells - pathology Female GPCR Humans Inflammation Inflammatory bowel disease Intestinal Mucosa - drug effects Intestinal Mucosa - immunology Intestinal Mucosa - pathology Life Sciences Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Middle Aged Neuropeptide NF-kappa B - immunology NF-kappa B - metabolism Orexin Receptor Antagonists - pharmacology Orexin Receptors - genetics Orexin Receptors - metabolism Orexins Orexins - pharmacology Orexins - therapeutic use Phenylurea Compounds - pharmacology Retrospective Studies Signal Transduction - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism Ulcerative colitis Young Adult Inflammatory bowel disease GPCR Inflammation Orexins Neuropeptide Ulcerative colitis
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Orexins (orexin-A and orexin-B) are hypothalamic peptides that are produced by the same precursor and are involved in sleep/wake control, which is mediated by two G protein-coupled receptor subtypes, OX1R and OX2R. Ulcerative colitis (UC) is an inflammatory bowel disease, (IBD) which is characterized by long-lasting inflammation and ulcers that affect the colon and rectum mucosa and is known to be a significant risk factor for colon cancer development. Based on our recent studies showing that OX1R is aberrantly expressed in colon cancer, we wondered whether orexin-A could play a role in UC. Immunohistochemistry studies revealed that OX1R is highly expressed in the affected colonic epithelium of most UC patients, but not in the non-affected colonic mucosa. Injection of exogenous orexin-A specifically improved the inflammatory symptoms in the two colitis murine models. Conversely, injection of inactive orexin-A analog, OxB7–28 or OX1R specific antagonist SB-408124 did not have anti-inflammatory effect. Moreover, treatment with orexin-A in DSS-colitis induced OX1R−/− knockout mice did not have any protective effect. The orexin-A anti-inflammatory effect was due to the decreased expression of pro-inflammatory cytokines in immune cells and specifically in T-cells isolated from colonic mucosa. Moreover, orexin-A inhibited canonical NFκB activation in an immune cell line and in intestinal epithelial cell line. These results suggest that orexin-A might represent a promising alternative to current UC therapies. •OX1R is highly expressed in human colonic mucosa from UC patients.•Injection of orexin-A improves inflammation symptoms in two murine.•Orexin-A down-regulates the pro-inflammatory cytokine production by immune cells isolated from colonic mucosa.•Orexin-A inhibits IL-8 secretion in immune cell line and in intestinal epithelial cell line.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0925-4439 1879-260X
DOI:	10.1016/j.bbadis.2018.08.023