Inhibition of the expression of inducible nitric oxide synthase and cyclooxygenase-2 in macrophages by 7HQ derivatives:: involvement of IκB-α stabilization

被引:8
作者
Huang, YC
Guh, JH
Cheng, ZJ
Chang, YL
Hwang, TL
Liao, CH
Tzeng, CC
Teng, CM [1 ]
机构
[1] Natl Taiwan Univ, Coll Med, Inst Pharmacol, Taipei, Taiwan
[2] Natl Taiwan Univ, Coll Med, Sch Pharm, Taipei 10018, Taiwan
[3] Kaohsiung Med Univ, Sch Chem, Kaohsiung, Taiwan
关键词
7HQ derivative; nitric oxide (NO) synthase; inducible; cyclooxygenase-2; macrophage;
D O I
10.1016/S0014-2999(01)00922-0
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Nitric oxide is an important biological mediator associated with multiple pathophysiological phenomena, such as platelet aggregation, vasodilation, septic shock, and autoimmune diseases. Prostaglandins, derived from cyclooxygenases, play prominent roles in homeostasis and inflammation. In this study, we characterized the effects of 7HQ derivatives (7-[(4-methylene-5-oxo-2-R-2-tetrahydrofuranyl)methoxy]-3,4-dihydrocarbostyril, where R is methyl, phenyl, p-fluorophenyl and p-phenylphenyl; 7HQ-1,-2,-3 and-if, respectively) in murine RAW 264.7 cells, a macrophage-like cell line. Lipopolysaccharide. the active component of endotoxin, significantly induced the expression of inducible nitric oxide synthase and cyclooxygenase-2, leading to the accumulation of nitrite and prostaglandin E-2, respectively. These actions of lipopolysaccharide wen inhibited by 7HQ derivatives; additionally, the inhibition of the expression, rather than the activity, of inducible nitric oxide synthase correlated well with that of nitric oxide formation. Western blotting and electrophoretic mobility shift assay results demonstrated that the 7HQ derivatives could effectively inhibit I kappaB-alpha degradation and nuclear factor kappaB (NF-kappaB) translocation. At higher concentrations, 7HQ derivatives also inhibited cyclooxygenase-2 enzyme activity. These results suggest that 7HQ derivatives exhibit inhibitory effects on lipopolysaccharide-induced nitric oxide production and expression of inducible nitric oxide synthase and cyclooxygenase-2 through inhibition of I kappaB-alpha degradation and NF-kappaB activation. (C) 2001 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:133 / 139
页数:7
相关论文
共 32 条
[1]   Oxidative stress and gene regulation [J].
Allen, RG ;
Tresini, M .
FREE RADICAL BIOLOGY AND MEDICINE, 2000, 28 (03) :463-499
[2]   IκB-NF-κB structures:: At the interface of inflammation control [J].
Baeuerle, PA .
CELL, 1998, 95 (06) :729-731
[3]   Mechanisms of disease - Nuclear factor-kappa b - A pivotal transcription factor in chronic inflammatory diseases [J].
Barnes, PJ ;
Larin, M .
NEW ENGLAND JOURNAL OF MEDICINE, 1997, 336 (15) :1066-1071
[4]   Lipopolysaccharide signal transduction, regulation of tumor necrosis factor biosynthesis, and signaling by tumor necrosis factor itself [J].
Beutler, B ;
Kruys, V .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1995, 25 :S1-S8
[5]   The role of IP prostanoid receptors in inflammatory pain [J].
Bley, KR ;
Hunter, JC ;
Eglen, RM ;
Smith, JAM .
TRENDS IN PHARMACOLOGICAL SCIENCES, 1998, 19 (04) :141-147
[6]  
Chen CC, 1999, MOL PHARMACOL, V55, P481
[7]  
Decker Karl, 1998, Keio Journal of Medicine, V47, P1
[8]  
DING AH, 1988, J IMMUNOL, V141, P2407
[9]   Cyclooxygenase in biology and disease [J].
Dubois, RN ;
Abramson, SB ;
Crofford, L ;
Gupta, RA ;
Simon, LS ;
Van De Putte, LBA ;
Lipsky, PE .
FASEB JOURNAL, 1998, 12 (12) :1063-1073
[10]   ANALYSIS OF NITRATE, NITRITE, AND [N-15]-LABELED NITRATE IN BIOLOGICAL-FLUIDS [J].
GREEN, LC ;
WAGNER, DA ;
GLOGOWSKI, J ;
SKIPPER, PL ;
WISHNOK, JS ;
TANNENBAUM, SR .
ANALYTICAL BIOCHEMISTRY, 1982, 126 (01) :131-138