TAK1 targeting by glucocorticoids determines JNK and IkappaB regulation in Toll-like receptor-stimulated macrophages

• Published in: Blood 2010-03, Vol.115 (10), p.1921-1931
• Main Authors: Bhattacharyya, Sandip, Ratajczak, Christine K, Vogt, Sherri K, Kelley, Crystal, Colonna, Marco, Schreiber, Robert D, Muglia, Louis J
• Format: Article
• Language: English
• Subjects: Animals; Dexamethasone - pharmacology; Drug Delivery Systems; Glucocorticoids - pharmacology; I-kappa B Proteins - metabolism; Immunity, Innate - drug effects; Immunity, Innate - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; Macrophage Activation - drug effects; Macrophage Activation - genetics; Macrophages - drug effects; Macrophages - metabolism; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Polydeoxyribonucleotides - pharmacology; Signal Transduction - drug effects; Signal Transduction - genetics; Toll-Like Receptor 3 - antagonists & inhibitors; Toll-Like Receptor 3 - metabolism; Toll-Like Receptor 9 - antagonists & inhibitors; Toll-Like Receptor 9 - metabolism; Toll-Like Receptors - agonists; Toll-Like Receptors - metabolism; Toll-Like Receptors - physiology
• ISSN: 1528-0020
• DOI: 10.1182/blood-2009-06-224782

Glucocorticoids potently attenuate the production of inflammatory mediators by macrophages, a primary effector of innate immunity. Activation of different macrophage Toll-like receptors (TLRs) by their respective ligands presents a powerful system by which to evaluate stimulus-dependent glucocorticoid effects in the same cell type. Here, we test the hypothesis that glucocorticoids, acting through the glucocorticoid receptor, modulate macrophage activation preferentially depending upon the TLR-selective ligand and TLR adapters. We established that 2 adapters, Trif, MyD88, or both, determine the ability of glucocorticoids to suppress inhibitor of kappaB (IkappaB) degradation or Janus kinase (JNK) activation. Moreover, the sensitivity of transforming growth factor beta-activated kinase 1 (TAK1) activation to glucocorticoids determines these effects. These findings identify TAK1 as a novel target for glucocorticoids that integrates their anti-inflammatory action in innate immunity signaling pathways.