Inhibition of IRAK1 Ubiquitination Determines Glucocorticoid Sensitivity for TLR9-Induced Inflammation in Macrophages.

Academic Article

Abstract

  • 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. β-TrCP-IRAK1 interaction is required for K48-linked ubiquitination of IRAK1 at Lys134 and subsequent membrane-to-cytoplasm trafficking of IRAK1 interacting partners TNFR-associated factor 6 and TAK1 that facilitates NF-κB 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 β-TrCP and IRAK1. Ablation of GR in macrophages prevents GC-dependent suppression of β-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 Lys134 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.

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    Keywords

  • Animals, Cells, Cultured, Cytokines, Glucocorticoids, Inflammation, Inflammation Mediators, Interleukin-1 Receptor-Associated Kinases, Macrophages, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, NF-kappa B, Protein Binding, Protein Transport, Toll-Like Receptor 9, Ubiquitination, beta-Transducin Repeat-Containing Proteins

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    Author List

  • Kong F; Liu Z; Jain VG; Shima K; Suzuki T; Muglia LJ; Starczynowski DT; Pasare C; Bhattacharyya S

    • Start Page

  • 3654

    • End Page

  • 3667

    • Volume

  • 199

    • Issue

  • 10