1. Division of Endocrinology and Metabolism, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA
2. Division of Nephrology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA
3. Division of Pulmonary and Critical Care Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA
4. Division of Cellular and Molecular Medicine, Department and School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA
5. Department of Medicinal Chemistry, Glaxo Wellcome Research and Development, P.O. Box 13398 Research Triangle Park, North Carolina 27709, USA
6. Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
7. These authors contributed equally to this work

Correspondence to: Christopher K. Glass⁷ Correspondence and requests for materials should be addressed to C.K.G. (e-mail: Email: cglass@ucsd.edu).

The peroxisome proliferator-activated receptor- (PPAR-) 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 function^{4, 5, 6}. PPAR- is activated by a range of synthetic and naturally occurring substances, including antidiabetic thiazolidinediones²,³, polyunsaturated fatty acids⁷, 15-deoxy-^12,14prostaglandin 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- 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_H2-derived cytokine interleukin-4 (ref. 11). Here we show that interleukin-4 also induces the expression of PPAR- and provide evidence that the coordinate induction of PPAR- 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-, and suggest a paradigm for the regulation of nuclear receptor function by cytokines.