The anti-inflammatory activity of Phellinus linteus (Berk. & M.A. Curt.) is mediated through the PKCdelta/Nrf2/ARE signaling to up-regulation of heme oxygenase-1.
It has been reported that heme oxygenase-1 (HO-1) mediates the anti-inflammatory activity of the n-BuOH subfraction (PL) prepared from fruiting bodies of Phellinus linteus. This continuing work aimed to elucidate the signaling pathway to the up-regulation of HO-1 by PL. In RAW264.7 macrophage cells, PL was able to enhance phosphorylation of protein kinase Cdelta (PKCdelta), but not PKCalpha/betaII, in a time-dependent manner. PL-induced HO-1 expression was dramatically released by GF109203X, a general inhibitor of PKC, and rottlerin, a specific PKCdelta inhibitor but not by Gö6976, a selective inhibitor for PKCalpha/beta. Additionally, PL treatment resulted in a marked increase in antioxidant response element (ARE)-driven transcriptional activity, which was dependent on PKCdelta but not PKCalpha. An increase by PL treatment in the ARE-driven transcriptional activity was further enhanced by Nrf2, whereas it was diminished by Keap1. Furthermore, pretreatment of rottlerin and overexpression of PKCdelta (K376R), a kinase-inactive form of PKCdelta, partly blocked the suppression by PL of nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression, and iNOS promoter activity, which were elevated in the lypopolysaccharide (LPS)-activated macrophages. Similarly, expression of matrix metalloproteinase-9 (MMP-9) and its promoter activity were suppressed by PL, which were dependent upon PKCdelta. The present findings indicate that Phellinus linteus gives rise to an anti-inflammatory activity though the PKCdelta/Nrf2/ARE signaling to the up-regulation of HO-1 in an in vitro inflammation model.
Kim
Byung-Chul
BC
Division of Life Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea. bckim@kangwon.ac.kr
Jeon
Woo-Kwang
WK
Hong
Hye-Young
HY
Jeon
Kyung-Bum
KB
Hahn
Jang-Hee
JH
Kim
Young-Myeong
YM
Numazawa
Satoshi
S
Yosida
Takemi
T
Park
Eun-Hee
EH
Lim
Chang-Jin
CJ
D000098:Acetophenones / Q000494:pharmacology; D000363:Agaricales / Q000737:chemistry*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
D000098:Acetophenones; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001578:Benzopyrans; D002227:Carbazoles; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; D061965:Matrix Metalloproteinase Inhibitors; D051267:NF-E2-Related Factor 2; C081021:Go 6976; D009569:Nitric Oxide; C085746:rottlerin; D008156:Luciferases; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D051745:Protein Kinase C-delta; D020780:Matrix Metalloproteinase 9; C070515:bisindolylmaleimide I