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Eur J Pharmacol. 2014 Jul 15;735:184-92. doi: 10.1016/j.ejphar.2014.04.024. Epub 2014 Apr 24.

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

Author information

  • 1College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
  • 2Department of Anatomy and Histology, Daegu Hany University, Gyeongsan 712-715, Republic of Korea.
  • 3Research and Development Center, Daewoo Pharm. Co. Ltd, Busan 604-836, Republic of Korea.
  • 4College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea. Electronic address: jakim@yu.ac.kr.

Abstract

Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, 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-α-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-α, IL-6), and chemokines (MCP-1, IL-8). In addition to inhibition of NF-κB nuclear translocation, SMA also caused significant suppression of TNF-α-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-κB activation pathways using SMA may be a good therapeutic intervention for the treatment of IBD.

Copyright © 2014 Elsevier B.V. All rights reserved.

KEYWORDS:

7-O-succinyl macrolactin A; Colitis; NF-κB; Rapamycin; mTOR

PMID:
24769511
[PubMed - indexed for MEDLINE]
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