Polyozellin Inhibits Nitric Oxide Production by Down-Regulating LPS-Induced Activity of NF-κB and SAPK/JNK in RAW 264.7 Cells

Abstract

Polyozellin, isolated from Polyozellus multiplex (Thelephoraceae), was investigated for its anti-inflammatory activity in the murine macrophage cell line RAW 264.7. Polyozellin inhibited both lipopolysaccharide (LPS)-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) gene expression in a dose-dependent manner. The effects of polyozellin on the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinases in these cells were studied in order to elucidate the underlying mechanism. Polyozellin suppressed the activation of both LPS-induced NF-κB and the stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), but had no effect on the extracellular signal-regulated kinase (ERK) or p38. These data suggest that polyozellin suppresses iNOS expression by inhibiting the activation of NF-κB and SAPK/JNK, leading to the inhibition of NO production.

References

• 1 Marletta M A. Nitric oxide synthase structure and mechanism.  J Biol Chem. 1993;  268 12 231-4
• 2 Zingarelli B, Squadrito F, Altavilla D, Calapei G, Campo G M, Calo M. et al . Evidence for a role of nitric oxide in hypovolemic hemorrhagic shock.  J Cardiovasc Pharmacol. 1992;  19 982-6
• 3 Kaur H, Halliwell B. Evidence for nitric oxide-mediated oxidative damage in chronic inflammation. Nitrotyrosine in serum and synovial fluid from rheumatoid patients.  FEBS Lett. 1994;  350 9-12
• 4 Ohshima H, Bartsch H. Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis.  Mutat Res. 1994;  305 253-64
• 5 Hwang J S, Song K S, Kim W G, Lee T H, Koshino H, Yoo I D. Polyozellin, a new inhibitor of prolyl endopeptidase from Polyozellus multiplex .  J Antibiot. 1997;  50 773-7
• 6 Chung S K, Jeon S Y, Lee H J, Kim S K, Kim S I, Kim G S. et al . Antioxidative effects of polyozellin and thelephoric acid isolated from Polyozellus multiplex .  J Korean Soc Appl Biol Chem. 2004;  47 283-6
• 7 Kim J H, Lee J S, Song K S, Kwon C S, Kim Y K, Kim J S. Polyozellin isolated from Polyozellus multiplex induces phase 2 enzymes in mouse hepatoma cells and differentiation in human myeloid leukaemic cell lines.  J Agric Food Chem. 2004;  52 451-5
• 8 Kim K M, Chun S B, Koo M S, Choi W J, Kim T W, Kwon Y G. et al . Differential regulation of NO availability from macrophages and endothelial cells by the garlic component S-allyl cysteine.  Free Radic Biol Med. 2001;  30 747-56
• 9 Banskota A H, Tezuka Y, Nguyen N T, Awale S, Nobukawa T, Kadota S. DPPH radical scavenging and nitric oxide inhibitory activities of the constituents from the wood of Taxus yunnanensis .  Planta Med. 2003;  69 500-5
• 10 Xie Q W, Kashiwabara Y, Nathan C. Role of transcription factor NF-κB/Rel in induction of nitric oxide synthase.  J Biol Chem. 1994;  269 4705-8
• 11 Karin M. The beginning of the end: IκB kinase (IKK) and NF-κB activation.  J Biol Chem. 1999;  274 27 339-42
• 12 Jang S I, Jeong S I, Kim K J, Kim H J, Yu H H, Park R. et al . Tanshinone IIA from Salvia miltiorrhiza inhibits inducible nitric oxide synthase expression and production of TNF-α, IL-1β and IL-6 in activated RAW 264.7 cells.  Planta Med. 2003;  69 1057-9
• 13 Sanghera J S, Weinstein S L, Aluwalia M, Girn J, Pelech S L. Activation of multiple proline-directed kinases by bacterial lipopolysaccharide in murine macrophages.  J Immunol. 1996;  156 4457-65
• 14 Caivano M. Role of MAP kinase cascades in inducing arginine transporters and nitric oxide synthetase in RAW264 macrophages.  FEBS Lett. 1998;  429 249-53
• 15 Kim Y H, Lee S H, Lee J Y, Choi S W, Park J W, Kwon T K. Triptolide inhibits murine-inducible nitric oxide synthase expression by down-regulating lipopolysaccharide-induced activity of nuclear factor-κB and c-Jun NH2-terminal kinase.  Eur J Pharmacol. 2004;  494 1-9
• 16 Hwang J S, Song K S, Kim Y S, Seok S J, Lee T H, Yoo I D. Lipid peroxidation inhibitors from Polyozellus multiplex .  Kor J Appl Microbiol Biotechnol. 1996;  24 591-6
• 17 Green L C, Wagner D A, Glogowski J, Skipper P L, Wishnok J S, Tannenbaum S R. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids.  Anal Biochem. 1982;  126 131-8
• 18 Lee S H, Seo G S, Sohn D H. Inhibition of lipopolysaccharide-induced expression of inducible nitric oxide synthase by butein in RAW 264.7 cells.  Biochem Biophys Res Commun. 2004;  323 125-32