Endogenous Epoxygenases Are Modulators of Monocyte/Macrophage Activity

被引:70
作者
Bystrom, Jonas [1 ]
Wray, Jessica A. [1 ]
Sugden, Mary C. [2 ]
Holness, Mark J. [2 ]
Swales, Karen E. [1 ]
Warner, Timothy D. [1 ]
Edin, Matthew L. [3 ]
Zeldin, Darryl C. [3 ]
Gilroy, Derek W. [4 ]
Bishop-Bailey, David [1 ]
机构
[1] Queen Mary Univ London, William Harvey Res Inst, London, England
[2] Queen Mary Univ London, Blizzard Inst Cell & Mol Sci, London, England
[3] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA
[4] UCL, Div Med, London, England
来源
PLOS ONE | 2011年 / 6卷 / 10期
基金
美国国家卫生研究院; 英国惠康基金;
关键词
PROLIFERATOR-ACTIVATED RECEPTORS; KAPPA-B ACTIVITY; ENDOTHELIAL-CELLS; LAMINAR-FLOW; IN-VITRO; CYTOCHROME-P450; ACID; EXPRESSION; CYP2J2; GAMMA;
D O I
10.1371/journal.pone.0026591
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Arachidonic acid is metabolized through three major metabolic pathways, the cyclooxygenase, lipoxygenase and CYP450 enzyme systems. Unlike cyclooxygenase and lipoxygenases, the role of CYP450 epoxygenases in monocyte/macrophage-mediated responses is not known. Methodology/Principal Findings: When transfected in vitro, CYP2J2 is an efficient activator of anti-inflammatory pathways through the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha. Human monocytes and macrophages contain PPAR alpha and here we show they express the epoxygenases CYP2J2 and CYP2C8. Inhibition of constitutive monocyte epoxygenases using the epoxygenase inhibitor SKF525A induces cyclooxygenase (COX)-2 expression and activity, and the release of TNF alpha, and can be reversed by either add back of the endogenous epoxygenase products and PPAR alpha ligand 11,12-epoxyeicosatrienoic acid (EET) or the addition of the selective synthetic PPAR alpha ligand GW7647. In alternatively activated (IL-4-treated) monocytes, in contrast to classically activated cells, epoxygenase inhibition decreased TNF alpha release. Epoxygenases can be pro-inflammatory via superoxide anion production. The suppression of TNF alpha by SKF525A in the presence of IL-4 was associated with a reduction in superoxide anion generation and reproduced by the superoxide dismutase MnCl2. Similar to these acute activation studies, in monocyte derived macrophages, epoxygenase inhibition elevates M1 macrophage TNF alpha mRNA and further decreases M2 macrophage TNF alpha. Conclusions/Significance: In conclusion, epoxygenase activity represents an important endogenous pathway which limits monocyte activation. Moreover endogenous epoxygenases are immuno-modulators regulating monocyte/macrophage activation depending on the underlying activation state.
引用
收藏
页数:8
相关论文
共 41 条
[1]  
ABRAMSON SL, 1990, J IMMUNOL, V144, P625
[2]  
BAIN B, 1972, TRANSPLANT P, V4, P163
[3]   DIFFERENTIAL-EFFECTS OF INTERLEUKIN-4 ON SUPEROXIDE ANION PRODUCTION BY HUMAN ALVEOLAR MACROPHAGES STIMULATED WITH LIPOPOLYSACCHARIDE AND INTERFERON-GAMMA [J].
BHASKARAN, G ;
NII, A ;
SONE, S ;
OGURA, T .
JOURNAL OF LEUKOCYTE BIOLOGY, 1992, 52 (02) :218-223
[5]   Peroxisome proliferator-activated receptors: a critical review on endogenous pathways for ligand generation [J].
Bishop-Bailey, D ;
Wray, J .
PROSTAGLANDINS & OTHER LIPID MEDIATORS, 2003, 71 (1-2) :1-22
[6]   Intimal smooth muscle cells as a target for peroxisome proliferator-activated receptor-γ ligand therapy [J].
Bishop-Bailey, D ;
Hla, T ;
Warner, TD .
CIRCULATION RESEARCH, 2002, 91 (03) :210-217
[7]   Identification of a subtype selective human PPARα agonist through parallel-array synthesis [J].
Brown, PJ ;
Stuart, LW ;
Hurley, KP ;
Lewis, MC ;
Winegar, DA ;
Wilson, JG ;
Wilkinson, WO ;
Ittoop, OR ;
Willson, TM .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (09) :1225-1227
[8]  
Campbell W.B., PFLUGERS ARCH, V459, P881
[9]  
Capdevila JH, 2000, J LIPID RES, V41, P163
[10]  
CHEN C, J PHARM EXP THER, V336, P344