Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase

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Abstract
The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-dependent nuclear receptor that has been implicated in the modulation of critical aspects of development and homeostasis, including adipocyte differentiation1, glucose metabolism2,3 and macrophage development and function4,5,6. PPAR-γ is activated by a range of synthetic and naturally occurring substances, including antidiabetic thiazolidinediones2,3, polyunsaturated fatty acids7, 15-deoxy-Δ12,14prostaglandin J2 (refs 8, 9) and components of oxidized low-density lipoprotein, such as 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE)10. However, the identities of endogenous ligands for PPAR-γ 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 (ref. 11). Here we show that interleukin-4 also induces the expression of PPAR-γ and provide evidence that the coordinate induction of PPAR-γ 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-γ, and suggest a paradigm for the regulation of nuclear receptor function by cytokines.