Anti-inflammatory effect of methylpenicinoline from a marine isolate of Penicillium sp. (SF-5995): inhibition of NF-κB and MAPK pathways in lipopolysaccharide-induced RAW264.7 macrophages and BV2 microglia.
In the course of a search for anti-inflammatory metabolites from marine-derived fungi, methylpenicinoline (1) was isolated from a marine isolate of Penicillin sp. Compound 1 inhibited lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production by suppressing the expression of inducible NO synthase (iNOS) in RAW264.7 macrophages and BV2 microglia. It also attenuated prostaglandin E2 (PGE2) production by suppressing cyclooxygenase-2 (COX-2) expression in a concentration-dependent manner (from 10 μM to 80 μM) without affecting cell viability. In addition, compound 1 reduced the production of the pro-inflammatory cytokine interleukin-1β (IL-1β). In a further study designed to elucidate the mechanism of its anti-inflammatory effects, compound 1 was shown to block nuclear factor-kappa B (NF-κB) activation in LPS-induced RAW264.7 macrophages and BV2 microglia by inhibiting the phosphorylation of inhibitor kappa B-α (IκB-α), thereby suppressing the nuclear translocation of NF-κB dimers, namely p50 and p65, that are known to be crucial molecules associated with iNOS and COX-2 expression. In addition, compound 1 inhibited the activation of mitogen-activated protein kinase (MAPK) pathways. Taken together, the results suggest that compound 1 might be a valuable therapeutic agent for the treatment of anti-inflammatory and anti-neuroinflammatory diseases.
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea. kimman07@hanmail.net.
Dong-Cheol
DC
Kim
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea. cutehs22@naver.com.
Hee-Suk
HS
Lee
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea. rabis815@naver.com.
Wonmin
W
Ko
Inha Research Institute for Medical Sciences, Inha University School of Medicine, Incheon 400-712, Korea. dongsunglee@inha.ac.kr.
Dong-Sung
DS
Lee
College of Medical and Life Sciences, Silla University, Busan 617-736, Korea. jhsohn@silla.ac.kr.
Jae Hak
JH
Sohn
Korea Polar Research Institute, KORDI, 7-50 Songdo-dong, Yeonsu-gu, Incheon 406-840, Korea. jhyim@kopri.re.kr.
Joung Han
JH
Yim
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea. yckim@wku.ac.kr.
Youn-Chul
YC
Kim
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea. hoh@wku.ac.kr.
Hyuncheol
H
Oh
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D059001:Aquatic Organisms / Q000737:chemistry*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010407:Penicillium / Q000737:chemistry*
D000893:Anti-Inflammatory Agents; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone