α-Chaconine isolated from a Solanum tuberosum L. cv Jayoung suppresses lipopolysaccharide-induced pro-inflammatory mediators via AP-1 inactivation in RAW 264.7 macrophages and protects mice from endotoxin shock.
In this study, we investigated the molecular mechanisms underlying the anti-inflammatory effects of α-chaconine in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and in LPS-induced septic mice. α-Chaconine inhibited the expressions of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) at the transcriptional level, and attenuated the transcriptional activity of activator protein-1 (AP-1) by reducing the translocation and phosphorylation of c-Jun. α-Chaconine also suppressed the phosphorylation of TGF-β-activated kinase-1 (TAK1), which lies upstream of mitogen-activated protein kinase kinase 7 (MKK7)/Jun N-terminal kinase (JNK) signaling. JNK knockdown using siRNA prevented the α-chaconine-mediated inhibition of pro-inflammatory mediators. In a sepsis model, pretreatment with α-chaconine reduced the LPS-induced lethality and the mRNA and production levels of pro-inflammatory mediators by inhibiting c-Jun activation. These results suggest that the anti-inflammatory effects of α-chaconine are associated with the suppression of AP-1, and support its possible therapeutic role for the treatment of sepsis.
Department of pharmaceutical Biochemistry, Kyung Hee University, Seoul, Republic of Korea.
Kyoung-Goo
KG
Lee
Department of pharmaceutical Biochemistry, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul, Republic of Korea.
Suel-Gie
SG
Lee
Department of pharmaceutical Biochemistry, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul, Republic of Korea.
Hwi-Ho
HH
Lee
Department of pharmaceutical Biochemistry, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul, Republic of Korea.
Hae Jun
HJ
Lee
Department of pharmaceutical Biochemistry, Kyung Hee University, Seoul, Republic of Korea; Reactive Oxygen Species Medical Research Center, School of Medicine, Kyung Hee University, Republic of Korea.
Ji-Sun
JS
Shin
Department of pharmaceutical Biochemistry, Kyung Hee University, Seoul, Republic of Korea.
Nan-Jung
NJ
Kim
Department of Pharmacology, College of Oriental Medicine, Sangji University, Wonju-si, Gangwon-do 220-702, Republic of Korea.
Hyo-Jin
HJ
An
Highland Agriculture Research Center, NICS, RDA, Pyeongchang 232-955, Republic of Korea.
Jung-Hwan
JH
Nam
Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul, Republic of Korea.
Dae Sik
DS
Jang
Department of pharmaceutical Biochemistry, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul, Republic of Korea. Electronic address: ktlee@khu.ac.kr.
Kyung-Tae
KT
Lee
D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004731:Endotoxins / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D048688:MAP Kinase Kinase 7; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D012992:Solanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011198:Solanum tuberosum / Q000737:chemistry*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004731:Endotoxins; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D012992:Solanine; C011860:alpha-chaconine; D051546:Cyclooxygenase 2; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7
AP-1; Inflammatory mediators; MKK7; Sepsis; α-Chaconine