TAK1 targeting by glucocorticoids determines JNK and IkappaB regulation in Toll-like receptor-stimulated macrophages.
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.
Bhattacharyya
Sandip
S
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. sandip.bhattacharyya@vanderbilt.edu
Ratajczak
Christine K
CK
Vogt
Sherri K
SK
Kelley
Crystal
C
Colonna
Marco
M
Schreiber
Robert D
RD
Muglia
Louis J
LJ
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D016503:Drug Delivery Systems; D005938:Glucocorticoids / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism*; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D008262:Macrophage Activation / Q000187:drug effects* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D000099151:MAP Kinase Kinase Kinase 7
D003907:Dexamethasone; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D011089:Polydeoxyribonucleotides; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D000099151:MAP Kinase Kinase Kinase 7; C519703:TLR3 protein, mouse; C495370:Tlr9 protein, mouse; C031156:poly d(I-C)