Protective effect of 7-O-succinyl macrolactin A against intestinal inflammation is mediated through PI3-kinase/Akt/mTOR and NF-κB signaling pathways.
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.
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
Sumin
S
Park
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
Sushil Chandra
SC
Regmi
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
Su-Young
SY
Park
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
Eun Kyoung
EK
Lee
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
Jae-Hoon
JH
Chang
Department of Anatomy and Histology, Daegu Hany University, Gyeongsan 712-715, Republic of Korea.
Sae Kwang
SK
Ku
Research and Development Center, Daewoo Pharm. Co. Ltd, Busan 604-836, Republic of Korea.
Dong-Hee
DH
Kim
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea. Electronic address: jakim@yu.ac.kr.
Jung-Ae
JA
Kim
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002448:Cell Adhesion; D002470:Cell Survival / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000473:pathology; D016207:Cytokines / Q000235:genetics; D005260:Female; D019073:HT29 Cells; D006801:Humans; D018942:Macrolides / Q000494:pharmacology* / Q000627:therapeutic use; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid; D020298:U937 Cells
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018942:Macrolides; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014302:Trinitrobenzenesulfonic Acid; C559723:7-O-succinyl macrolactin A; C546842:MTOR protein, human
7-O-succinyl macrolactin A; Colitis; NF-κB; Rapamycin; mTOR