TAK1 targeting by glucocorticoids determines JNK and IκB regulation in toll-like receptor-stimulated macrophages

Sandip Bhattacharyya, Christine K. Ratajczak, Sherri K. Vogt, Crystal Kelley, Marco Colonna, Robert D. Schreiber, Louis J. Muglia

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

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 κB (IκB) degradation or Janus kinase (JNK) activation. Moreover, the sensitivity of transforming growth factor β-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.

Original languageEnglish
Pages (from-to)1921-1931
Number of pages11
JournalBlood
Volume115
Issue number10
DOIs
StatePublished - Mar 11 2010

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