Torilin Inhibits Inflammation by Limiting TAK1-Mediated MAP Kinase and NF-κB Activation.
Torilin, a sesquiterpene isolated from the fruits ofTorilis japonica,has shown antimicrobial, anticancer, and anti-inflammatory properties. However, data on the mechanism of torilin action against inflammation is limited. This study aimed at determining the anti-inflammatory property of torilin in LPS-induced inflammation using in vitro model of inflammation. We examined torilin's effect on expression levels of inflammatory mediators and cytokines in LPS-stimulated RAW 264.7 macrophages. The involvement of NF-kB and AP-1, MAP kinases, and adaptor proteins were assessed. Torilin strongly inhibited LPS-induced NO release, iNOS, PGE2, COX-2, NF-α, IL-1β, IL-6, and GM-CSF gene and protein expressions. In addition, MAPKs were also suppressed by torilin pretreatment. Involvement of ERK1/2, P38MAPK, and JNK1/2 was further confirmed by PD98059, SB203580, and SP600125 mediated suppression of iNOS and COX-2 proteins. Furthermore, torilin attenuated NF-kB and AP-1 translocation, DNA binding, and reporter gene transcription. Interestingly, torilin inhibited TAK1 kinase activation with the subsequent suppression of MAPK-mediated JNK, p38, ERK1/2, and AP-1 (ATF-2 and c-jun) activation and IKK-mediated I-κBαdegradation, p65/p50 activation, and translocation. Together, the results revealed the suppression of NF-κB and AP-1 regulated inflammatory mediator and cytokine expressions, suggesting the test compound's potential as a candidate anti-inflammatory agent.
Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
Mehari
0000-0002-1224-9415
M
Endale
College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea.
Tae-Hwan
TH
Kim
Research and Development Headquarters, Korea Ginseng Corporation, Daejon 305-805, Republic of Korea.
Yi-Seong
YS
Kwak
Research and Development Headquarters, Korea Ginseng Corporation, Daejon 305-805, Republic of Korea.
Na-Mi
NM
Kim
Institute of Traditional Medicine & Bioscience, Daejeon University, Daejeon 300-716, Republic of Korea.
Seung-Hyung
SH
Kim
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Jae Youl
0000-0001-8141-9927
JY
Cho
College of Environmental & Bioresource Sciences, Chonbuk National University, Iksan 570-752, Republic of Korea.
Bong-Sik
0000-0002-0594-8955
BS
Yun
College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea.
Man-Hee
0000-0002-3088-1318
MH
Rhee
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D045789:Sesquiterpenes, Guaiane / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000099151:MAP Kinase Kinase Kinase 7
D000893:Anti-Inflammatory Agents; D051546:Cyclooxygenase 2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D053583:Interleukin-1beta; D015850:Interleukin-6; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D045789:Sesquiterpenes, Guaiane; D000099151:MAP Kinase Kinase Kinase 7; C112694:torilin