| First Author | Kong F | Year | 2015 |
| Journal | Immunology | Volume | 145 |
| Issue | 1 | Pages | 136-49 |
| PubMed ID | 25521315 | Mgi Jnum | J:246417 |
| Mgi Id | MGI:5924020 | Doi | 10.1111/imm.12434 |
| Citation | Kong F, et al. (2015) Transforming growth factor-beta-activated kinase 1 resistance limits glucocorticoid responsiveness to Toll-like receptor 4-mediated inflammation. Immunology 145(1):136-49 |
| abstractText | 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-beta-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-alpha 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. |
