Adrenomedullin treatment reduces intestinal inflammation and maintains epithelial barrier function in mice administered dextran sulphate sodium.
Hyperactivation and hyperpermeability of the intestinal epithelium is a hallmark of IBD. AM has been shown to reduce the severity of colitis in the acetic acid and TNBS-induced colitis model, however the mechanism of the therapeutic effect of AM against the colitis has not been clarified. Here, we show that the protective capability of AM is associated with suppression of inflammation and maintenance of the intestinal epithelial barrier function. In the DSS-induced colitis model, intra-rectal AM-treated mice showed a reduction in loss of body weight and severity of colitis. AM-treatment suppressed phosphorylation of STAT1 and STAT3 in the colonic epithelium, and altered the cytokine balance in the intestinal T cells, with lower levels of IFN-gamma and TNF-alpha but higher levels of TGF-beta. Expression of the epithelial intercellular junctions such as tight and adherence junctions were sustained in the AM-treated mice. In contrast, the epithelial junctions were down-regulated in the control mice, leading to loss of epithelial barrier integrity and enhanced permeability. Collectively, these data indicate a broad spectrum of AM-induced effects with respect to protection against DSS-induced colitis, and suggest a potential therapeutic value of this treatment for IBD.
Ashizuka
Shinya
S
First Department of Internal Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan.
Inagaki-Ohara
Kyoko
K
Kuwasako
Kenji
K
Kato
Johji
J
Inatsu
Haruhiko
H
Kitamura
Kazuo
K
D000285:Administration, Rectal; D053607:Adrenomedullin / Q000008:administration & dosage*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014665:Vasodilator Agents / Q000008:administration & dosage*
D015815:Cell Adhesion Molecules; D016207:Cytokines; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D014665:Vasodilator Agents; D053607:Adrenomedullin; D016264:Dextran Sulfate