Document Detail

Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase.
MedLine Citation:
PMID:  10432118     Owner:  NLM     Status:  MEDLINE    
The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-dependent nuclear receptor that has been implicated in the modulation of critical aspects of development and homeostasis, including adipocyte differentiation, glucose metabolism and macrophage development and function. PPAR-gamma is activated by a range of synthetic and naturally occurring substances, including antidiabetic thiazolidinediones, polyunsaturated fatty acids, 15-deoxy-delta prostaglandin J2 and components of oxidized low-density lipoprotein, such as 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE). However, the identities of endogenous ligands for PPAR-gamma and their means of production in vivo have not been established. In monocytes and macrophages, 13-HODE and 15-HETE can be generated from linoleic and arachidonic acids, respectively, by a 12/15-lipoxygenase that is upregulated by the TH2-derived cytokine interleukin-4. Here we show that interleukin-4 also induces the expression of PPAR-gamma and provide evidence that the coordinate induction of PPAR-gamma and 12/15-lipoxygenase mediates interleukin-4-dependent transcription of the CD36 gene in macrophages. These findings reveal a physiological role of 12/15-lipoxygenase in the generation of endogenous ligands for PPAR-gamma, and suggest a paradigm for the regulation of nuclear receptor function by cytokines.
J T Huang; J S Welch; M Ricote; C J Binder; T M Willson; C Kelly; J L Witztum; C D Funk; D Conrad; C K Glass
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Nature     Volume:  400     ISSN:  0028-0836     ISO Abbreviation:  Nature     Publication Date:  1999 Jul 
Date Detail:
Created Date:  1999-08-16     Completed Date:  1999-08-16     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  378-82     Citation Subset:  IM    
Department and School of Medicine, University of California, San Diego, La Jolla 92093-0651, USA.
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MeSH Terms
Antigens, CD36 / biosynthesis,  genetics*
Arachidonate 12-Lipoxygenase / metabolism*
Arachidonate 15-Lipoxygenase / metabolism*
Cell Line
Gene Expression Regulation
Interleukin-4 / physiology*
Macrophages / metabolism*
Mice, Knockout
Receptors, Cytoplasmic and Nuclear / biosynthesis,  genetics,  metabolism*
Transcription Factors / biosynthesis,  genetics,  metabolism*
Reg. No./Substance:
0/Antigens, CD36; 0/Ligands; 0/Receptors, Cytoplasmic and Nuclear; 0/Transcription Factors; 207137-56-2/Interleukin-4; EC 12-Lipoxygenase; EC 15-Lipoxygenase

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