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

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(1), glucose metabolism(2,3) and macrophage development and function(4-6). PPAR-gamma is activated by a range of synthetic and naturally occurring substances, including antidiabetic thiazolidinediones(2,3), polyunsaturated fatty acids(7), 15-deoxy-Delta(12,14)prostaglandin J(2) (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-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 T(H)2-derived cytokine interleukin-4 (ref. 11). 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.