title: Transforming growth factor-β-activated kinase 1 resistance limits glucocorticoid responsiveness to Toll-like receptor 4-mediated inflammation.
abstract: Glucocorticoids (GC) are among the most effective anti-inflammatory drugs, but are often associated with serious adverse effects or inadequate therapeutic responses. Here, we use activation of different Toll-like receptors (TLRs) by their respective ligands to evaluate context-specific GC sensitivity in the macrophage. Recruitment and activation of transforming growth factor-β-activated kinase 1 (TAK1), downstream of TLR engagement, is crucial in activating multiple inflammatory pathways, and contributes to inflammatory disorders. We hypothesize that GC exert anti-inflammatory effects through regulation of TAK1. Both in vivo and in vitro, in comparison to other TLRs, there was limited GC potency in restricting TLR4 ligand-mediated secretion of interleukin-6, tumour necrosis factor-α and interleukin-12. Also, we found that inactivation of TAK1 both in vivo and in vitro strongly inhibits TLR4-induced inflammation-associated genes beyond the suppressive effects from GC treatment. However, there was no effect of TAK1 inactivation on GC inhibition of TLR3- or TLR9-initiated inflammatory actions. Together, our findings demonstrate that GC resistance for TAK1 activation associated with TLR4 engagement may be an important contributor to GC resistance in inflammatory disorders.
authors.affiliation: Department of Pediatrics, Center for Prevention of Preterm Birth, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Fansheng
authors.initials: F
authors.lastname: Kong
authors.forename: Gloria
authors.initials: G
authors.lastname: Laryea
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Liu
authors.forename: Sandip
authors.initials: S
authors.lastname: Bhattacharyya
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology; D004351:Drug Resistance / Q000276:immunology*; D005938:Glucocorticoids / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D051379:Mice; D051196:Toll-Like Receptor 3 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D020930:MAP Kinase Kinase Kinases; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D000099151:MAP Kinase Kinase Kinase 7; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse
keywords: inflammation; protein kinases/phosphatases; signal transduction; toll-like receptors