A Novel Peroxisome Proliferator-activated Receptor (PPAR)γ Agonist 2-Hydroxyethyl 5-chloro-4,5-didehydrojasmonate Exerts Anti-Inflammatory Effects in Colitis.
Inflammatory bowel disease (IBD) is a chronic inflammatory disease with increasing incidence and prevalence worldwide. Here we investigated the newly synthesized jasmonate analogue 2-hydroxyethyl 5-chloro-4,5-didehydrojasmonate (J11-Cl) for its anti-inflammatory effects on intestinal inflammation. First, to test whether J11-Cl can activate peroxisome proliferator-activated receptors (PPARs), we performed docking simulations because J11-Cl has a structural similarity with anti-inflammatory 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2), one of the endogenous ligands of PPARγ. J11-Cl bound to the ligand binding domain of PPARγ in the same manner as 15d-PGJ2 and rosiglitazone, and significantly increased transcriptional activity of PPARγ. In animal experiments, colitis was significantly reduced in mice with J11-Cl treatment, determined by analyses of survival rate, body weight changes, clinical symptoms, and histological evaluation. Moreover, J11-Cl decreased production of pro-inflammatory cytokines including IL-6, IL-8, and G-CSF as well as chemokines including chemokine (C-C motif) ligand (CCL)20, chemokine (C-X-C motif) ligand (CXCL)2, CXCL3, and chemokine (C-X3-C motif) ligand 1 (CX3CL1) in colon tissues, and LPS or TNF-α-stimulated macrophages and epithelial cells. In contrast, production of anti-inflammatory cytokines including IL-2 and IL-4 as well as the proliferative factor, GM-CSF, was increased by J11-Cl. Furthermore, inhibition of MAPKs and NF-κB activation by J11-Cl was also observed. J11-Cl reduced intestinal inflammation by increasing the transcriptional activity of PPARγ and modulating inflammatory signaling pathways. Therefore, our study suggests that J11-Cl may serve as a novel therapeutic agent against IBD.
From the College of Pharmacy, Pusan National University, Busan, 609-735, Korea.
Jieun
J
Choo
From the College of Pharmacy, Pusan National University, Busan, 609-735, Korea.
Yunna
Y
Lee
College of Pharmacy, Harbin University of Commerce, Harbin, Heilongjiang Province 150076, P.R. China, and.
Xin-Jia
XJ
Yan
From the College of Pharmacy, Pusan National University, Busan, 609-735, Korea.
Tae Hwan
TH
Noh
From the College of Pharmacy, Pusan National University, Busan, 609-735, Korea.
Seong Jin
SJ
Kim
From the College of Pharmacy, Pusan National University, Busan, 609-735, Korea.
Sujin
S
Son
Section of Inflammatory Bowel Disease & Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095.
Charalabos
C
Pothoulakis
From the College of Pharmacy, Pusan National University, Busan, 609-735, Korea.
Hyung Ryong
HR
Moon
From the College of Pharmacy, Pusan National University, Busan, 609-735, Korea.
Jee H
JH
Jung
From the College of Pharmacy, Pusan National University, Busan, 609-735, Korea, eoim@pusan.ac.kr.
Eunok
E
Im
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003092:Colitis / Q000517:prevention & control*; D003517:Cyclopentanes / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054883:Oxylipins / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists*; D014158:Transcription, Genetic / Q000187:drug effects
C000604909:2-hydroxyethyl 5-chloro-4,5-didehydrojasmonate; D000893:Anti-Inflammatory Agents; D003517:Cyclopentanes; D054883:Oxylipins; D047495:PPAR gamma
NF-kappa B (NF-κB); colitis; cytokine; inflammatory bowel disease (IBD); mitogen-activated protein kinase (MAPK); peroxisome proliferator-activated receptor (PPAR)