Protective effect of 7-O-succinyl macrolactin A against intestinal inflammation is mediated through PI3-kinase/Akt/mTOR and NF-kappa B signaling pathways

Title
Protective effect of 7-O-succinyl macrolactin A against intestinal inflammation is mediated through PI3-kinase/Akt/mTOR and NF-kappa B signaling pathways
Author(s)
김정애박수민수실렉미박수영이은경장재훈구세광[구세광]김동희[김동희]
Keywords
TUMOR-NECROSIS-FACTOR; INTERCELLULAR-ADHESION MOLECULE-1; VANCOMYCIN-RESISTANT ENTEROCOCCI; SULFATE-INDUCED COLITIS; BOWEL-DISEASE; CROHNS-DISEASE; ULCERATIVE-COLITIS; TNF-ALPHA; STAPHYLOCOCCUS-AUREUS; T-CELLS
Issue Date
201407
Publisher
ELSEVIER SCIENCE BV
Citation
EUROPEAN JOURNAL OF PHARMACOLOGY, v.735, pp.184 - 192
Abstract
Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, are pivotal for the development of inflammatory bowel disease (IBD), and down-regulation of the cytokines and cytokine-induced inflammatory responses therefore constitute pharmacological targets for the development of therapeutic strategies in IBD. In the current study, we found that 7-O-succinyl macrolactin A (SMA), a macrolide, potently inhibited TNF-alpha-induced adhesion of monocytes to colonic epithelial cells in a concentration-dependent manner, similar to rapamycin, a mTOR inhibitor. In addition, oral administration of SMA resulted in a significant suppression of clinical signs of TNBS-induced rat colitis, including weight loss, colon tissue edema, and myeloperoxidase activity, a marker for inflammatory cell infiltration, as well as microscopic damage score in a histomorphological examination of HE-stained colon tissue. More importantly, SMA was more efficacious in inhibition of intestinal inflammation than 5-aminosalicylic acid (5-ASA), an active metabolite of sulfasalazine, the most commonly prescribed agent for the treatment of IBD. Such anti-inflammatory activity showed correlation with significant suppression of adhesion molecules (ICAM-1 and VCAM-1), T-helper 1-type cytokines (TNF-alpha, IL-6), and chemokines (MCP-1, IL-8). In addition to inhibition of NF-kappa B nuclear translocation, SMA also caused significant suppression of TNF-alpha-induced phosphorylation of PI3K, Akt, mTOR and p70S6 kinase, similar to the effect of rapamycin, an immunosuppressant macrolide. Taken together, the current results suggest that managing both mTOR and NF-kappa B activation pathways using SMA may be a good therapeutic intervention for the treatment of IBD. (C) 2014 Elsevier B.V. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/31472http://dx.doi.org/10.1016/j.ejphar.2014.04.024
ISSN
0014-2999
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약학대학 > 약학부 > Articles
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