Lucidone Inhibits iNOS and COX-2 Expression in LPS-Induced RAW 264.7 Murine Macrophage Cells via NF-κB and MAPKs Signaling Pathways

Abstract

The anti-inflammatory mechanism of lucidone isolated from the fruits of Lindera erythrocarpa Makino was investigated. Our data indicate that lucidone significantly inhibits the production of NO and PGE₂ autacoids in LPS-induced RAW 264.7 murine macrophage cells. Moreover, it also notably decreased the secretion of tumor necrosis factor-alpha (TNF-α). Consistent with these observations, the mRNA and protein expression levels of iNOS and COX-2 were also inhibited by lucidone in a dose-dependent manner. Lucidone also reduced the translocation of NF-κB induced by LPS, which is associated with the prevention of the degradation of I-κB, and subsequently decreased p65/p50 protein levels in the nucleus. Lucidone also inhibited NF-κB activation by impairing the binding of NF-κB to its cis-acting element. In addition, lucidone inhibited JNK and p38MAPKs signals, which are the most significant signals involved in NO, PGE₂ and TNF-α production; NF-κB/AP-1 activation was also inhibited by lucidone. Taken together, the anti-inflammatory activity of lucidone might be caused by the inhibition of iNOS and COX-2 expressions through downregulation of NF-κB and AP-1 binding.

Key words

Lindera erythrocarpa - Lauraceae - lucidone - anti‐inflammatory activity - NF‐κB - MAPKs

References

• 1 Lee K H. Current development in the discovery and design of new drug candidates from plant natural product leads.  J Nat Prod. 2004;  67 273-283
• 2 Newman D J, Cragg G M, Snader K M. Natural products as sources of new drugs over the period 1981–2002.  J Nat Prod. 2003;  66 1022-1083
• 3 Park H J, Kim I T, Won J H, Jeong S H, Park E Y, Nam J H, Choi J, Lee K T. Anti-inflammatory activities of ent-16αH,17-hydroxykauran-19-oic acid isolated from the roots of Siegesbeckia pubescens are due to the inhibition of iNOS and COX‐2 expression in RAW 264.7 macrophages via NF-κB inactivation.  Eur J Pharmacol. 2007;  558 185-193
• 4 Chiang Y M, Lo C P, Chen Y P, Wang S Y, Yang N S, Kou Y H, Shyur L F. Ethyl coffeate suppresses NF-κB activation and its downstream inflammatory mediators, iNOS, COX‐2, and PGE₂ in vitro or in mouse skin.  Br J Pharmacol. 2005;  146 352-363
• 5 Israf D A, Khaizurin T A, Lajis N H, Khozirah S. Cardamonin inhibits COX and iNOS expression via inhibition of p65NF-κB nuclear translocation and Iκ‐B phosphorylation in RAW 264.7 macrophage cells.  Mol Immunol. 2007;  44 673-679
• 6 Park J S, Lee E J, Lee J C, Kim W K, Kim H S. Anti-inflammatory effects of short chain fatty acids in IFN-γ-stimulated RAW 264.7 murine macrophage cells: Involvement of NF-κB and ERK signaling pathways.  Int Immunopharmacol. 2007;  7 70-77
• 7 Tsai S H, Lin-Shiau S Y, Lin J K. Suppression of nitric oxide synthase and the down-regulation of the activation of NF-κB in macrophages by resveratrol.  Br J Pharmacol. 1999;  126 673-680
• 8 Kundu J K, Surh Y J. Breaking the relay in deregulated cellular signal transduction as a rationale for chemo prevention with anti-inflammatory phytochemicals.  Mutat Res. 2005;  591 123-146
• 9 Shaulian E, Karin M. AP‐1 as a regulator of cell life and death.  Nat Cell Biol. 2002;  4 131-136
• 10 Lee J C, Laydon J T, McDonnel P C, Gallagher T F, Kumar S, Green, McNulty D, Blumenthal M J, Heys J R, Landvatter S W, Strickler J E, McLaughlin M M, Siemens I R, Fisher S M, Livi G P, White J R, Adams J L, Young P R. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.  Nature. 1994;  372 739-746
• 11 Komae H, Hayashi N. Terpenes from Lindera erythrocarpa.  Phytochemistry. 1972;  11 853
• 12 Liu S Y, Hisada S, Inagaki I. Terpenes of Linera erythocarpa.  Phytochemistry. 1973;  12 233
• 13 Ichino K, Tanaka H, Ito K. Two new dihydrochalcones from Lindera erythocarpa.  J Nat Prod. 1988;  51 915-917
• 14 Lin C T, Chu F H, Tseng Y H, Tsai J B, Chang S T, Wang S Y. Bioactivity investigation of Lauraceae trees grown in Taiwan.  Pharm Biol. 2007;  45 638-644
• 15 Oh H M, Chi S K, Lee J M, Lee S K, Kim H Y, Han D C, Kim H K, Kim H M, Son K H, Kwon B M. Cyclopentendiones inhibitors of farnesyl protein transferase and anti-tumor compounds, isolated from the fruits of Lindera erythocarpa Makino.  Bioorg Med Chem. 2005;  13 6182-6187
• 16 Wang S Y, Lan X Y, Xiao J-H, Yang J C, Kao Y T, Chang S T. Anti-inflammatory activity of Lindera erythrocarpa fruits.  Phytother Res. 2008;  22 213-216
• 17 Pan M H, Lai C S, Wang Y J, Ho C T. Acacetin suppressed LPS-induced up-expression of iNOS and COX‐2 in murine macrophages and TPA-induced tumor promotion in mice.  Biochem Pharmacol. 2006;  72 1293-1303
• 18 Hou D X, Lio D, Tanigwa S, Hashimoto F, Uto T, Masuzaki S, Fujii M, Sakata Y. Prodelphinidin B‐4 3′-O-gallate, a tea polyphenol, is involved in the inhibition of COX‐2 and iNOS via the downregulation of TAK1-NF-κB pathway.  Biochem Pharmacol. 2007;  74 742-751
• 19 Huh J E, Yim J H, Lee H K, Moon E Y, Rhee D K, Pyo S. Prodigiosin isolated from Hahella chejuensis suppresses lipopolysaccharide-indued NO production by inhibiting p 38 MAPK, JNK and NF-κB activation in murine peritoneal macrophages.  Int Immunopharmacol. 2007;  7 1825-1833
• 20 Laura C B, Isabel V, Juan M SC, Elena T, Susan S F, Virginia M, Lastra C A. Curcumin, a Curcuma longa constituent, acts on MAPK p 38 pathway modulating COX‐2 and iNOS expression in chronic experimental colitis.  Int Immunopharmacol. 2007;  7 333-342