Nuclear Receptors and c-JUN NH2-Terminal Kinase: Crosstalk and Actions

Abstract

The nuclear receptors (NR) modulate gene transcription in a ligand-dependent manner throughout different mechanisms. A set of NR, including PPARγ and LXR, are important regulators of carbohydrate and lipid metabolism as well as the immune system. In this regard, both PPARγ and LXR agonists ameliorate obesity-associated insulin resistance and show anti- inflammatory activity. The c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinases (MAPKs), is also involved in the metabolic and immune system regulation but in contrast to PPARγ and LXR, JNK activation promotes insulin resistance and triggers the inflammatory response. Due to theses opposite actions, an intense and negative crosstalk exists between these NR and the JNK pathway. In this regard, the PPARγ ligands TZDs perform their insulin sensitizing action through the inhibition of obesity-induced JNK activation. Therefore, in this study we aimed to develop an in vivo model for specific activation of JNK in myelod cells to study PPARγ and LXR on the JNK-induced inflammatory response. These mouse model was obtained by crossing mice from a transgenic strain generated in our group, which is able to induce the expression of a JNK activator in a Cre recombinase-dependent manner, with the LysMCre mice. In addition, since PPARγ and LXR interaction with the JNK pathway seems to require transcription, we have tested several PPARγ and LXR target genes as candidate mediators in this crosstalk.