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Transforming growth factor‐β‐activated kinase 1 resistance limits glucocorticoid responsiveness to Toll‐like receptor 4‐mediated inflammation
Author(s) -
Kong Fansheng,
Laryea Gloria,
Liu Zhiwei,
Bhattacharyya Sandip
Publication year - 2015
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12434
Subject(s) - tlr4 , inflammation , in vivo , proinflammatory cytokine , tumor necrosis factor alpha , toll like receptor , interleukin 1 receptor , receptor , context (archaeology) , biology , cancer research , pharmacology , immunology , cytokine , interleukin , innate immune system , biochemistry , microbiology and biotechnology , paleontology
Summary 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 vit ro 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.