Ameliorating effect of TI-1-162, a hydroxyindenone derivative, against TNBS-induced rat colitis is mediated through suppression of RIP/ASK-1/MAPK signaling

作者：Gurung Pallavi; Banskota Suhrid; Katila Nikita; Gautam Jaya; Kadayat Tara Man; Choi Dong Young; Lee Eung Seok; Jeong Tae Cheon; Kim Jung Ae^*

来源：European Journal of Pharmacology, 2018, 827: 94-102.

DOI：10.1016/j.ejphar.2018.03.027

• Inflammatory bowel disease (IBD)
• TNF-alpha
• RIP-1
• ASK-1
• Epithelial apoptosis
• Hydroxyindenone derivative TI-1-162

The pathogenesis of inflammatory bowel disease (IBD) is associated with production of immense pro-inflammatory cytokines including TNF-alpha. Once generated, TNF-alpha stimulates production of various pro-inflammatory cytokines and disrupts mucosal barrier by inducing inflamed mucosal epithelial cell death. In the present study, we investigated inhibitory effects of TI-1-162, a hydroxyindenone derivative, against TNF-alpha-induced and TNBS-induced colon inflammation. TI-1-162 showed inhibitory effect on the TNF-alpha-induced adhesion of U937 monocytic cells to HT-29 colonic epithelial cells (IC50 = 0.83 +/- 0.12 mu M), which is an in vitro model representing the initial step of colitis. In addition, TI-1-162 suppressed TNF-alpha-stimulated caspase-3 activation and HT-29 cell apoptosis. These in vitro inhibitory activities of TI-1-162 correlated to recovery changes in in vivo colon tissues, such as downregulation of adhesion molecules (ICAM-1, VCAM-1) and chemokines (CCL11, CXCL1, CXCL2, CXCL3, CX3CL1) revealed by gene expression array and Western blot analyses. Such molecular recovery of colon epithelium from TNBS-treated rats corresponded to the recovery in body weight, colon weight/length, and myeloperoxidase level by TI-1-162 (10 and 30 mg/kg/day, orally). In relation to action mechanism, TI-1-162 did not disturb TNF-alpha binding to its receptor, but suppressed phosphorylation of RIP-1, ASK-1, JNK and p38, and nuclear translocation of NF-kB and AP-1, which corresponded to down regulation of inflammatory cytokines in TNF-alpha-treated cells (HT-29 and U937) and TNBS-treated rat colon tissues. Taken together, the results indicate that the protective effects of TI-1-162 against colon inflammation and epithelial cell death are associated with its inhibitory action in RIP/ASK-1/MAPK signaling pathway downstream to TNF receptor 1.

• 出版日期2018-5-15