| First Author | Kong F | Year | 2017 |
| Journal | J Immunol | Volume | 199 |
| Issue | 10 | Pages | 3654-3667 |
| PubMed ID | 29038250 | Mgi Jnum | J:251197 |
| Mgi Id | MGI:6104430 | Doi | 10.4049/jimmunol.1700443 |
| Citation | Kong F, et al. (2017) Inhibition of IRAK1 Ubiquitination Determines Glucocorticoid Sensitivity for TLR9-Induced Inflammation in Macrophages. J Immunol 199(10):3654-3667 |
| abstractText | Inflammatory responses are controlled by signaling mediators that are regulated by various posttranslational modifications. Recently, transcription-independent functions for glucocorticoids (GC) in restraining inflammation have emerged, but the underlying mechanisms are unknown. In this study, we report that GC receptor (GR)-mediated actions of GC acutely suppress TLR9-induced inflammation via inhibition of IL-1R-associated kinase 1 (IRAK1) ubiquitination. beta-TrCP-IRAK1 interaction is required for K48-linked ubiquitination of IRAK1 at Lys(134) and subsequent membrane-to-cytoplasm trafficking of IRAK1 interacting partners TNFR-associated factor 6 and TAK1 that facilitates NF-kappaB and MAPK activation. Upon costimulation of macrophages with GC and TLR9-engaging ligand, GR physically interacts with IRAK1 and interferes with protein-protein interactions between beta-TrCP and IRAK1. Ablation of GR in macrophages prevents GC-dependent suppression of beta-TrCP-IRAK1 interactions. This GC-mediated suppression of IRAK1 activation is unique to TLR9, as GC treatment impairs TLR9 but not TLR4 ligand-induced K48-linked IRAK1 ubiquitination and trafficking of IRAK1 interacting partners. Furthermore, mutations in IRAK1 at Lys(134) prevent TLR9 ligand-induced activation of inflammatory signaling mediators and synthesis of proinflammatory cytokines to an extent comparable to GC-mediated inhibition. Collectively, these findings identify a transcription-independent, rapid, and nongenomic GC suppression of TLR9 ligand-mediated IRAK1 ubiquitination as a novel mechanism for restraining acute inflammatory reactions. |
