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IRAK4 kinase activity controls Toll-like receptor-induced inflammation through the transcription factor IRF5 in primary human monocytes.
Cushing, Leah; Winkler, Aaron; Jelinsky, Scott A; Lee, Katherine; Korver, Wouter; Hawtin, Rachael; Rao, Vikram R; Fleming, Margaret; Lin, Lih-Ling.
Afiliação
  • Cushing L; From the Departments of Inflammation and Immunology and.
  • Winkler A; From the Departments of Inflammation and Immunology and.
  • Jelinsky SA; From the Departments of Inflammation and Immunology and.
  • Lee K; Medicinal Chemistry, Pfizer Inc., Cambridge, Massachusetts 02139 and.
  • Korver W; Nodality Inc., South San Francisco, California 94080.
  • Hawtin R; Nodality Inc., South San Francisco, California 94080.
  • Rao VR; From the Departments of Inflammation and Immunology and.
  • Fleming M; From the Departments of Inflammation and Immunology and.
  • Lin LL; From the Departments of Inflammation and Immunology and lih-ling.lin@pfizer.com.
J Biol Chem ; 292(45): 18689-18698, 2017 11 10.
Article em En | MEDLINE | ID: mdl-28924041
Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate immune signaling by Toll-like receptors (TLRs), and loss of IRAK4 activity in mice and humans increases susceptibility to bacterial infections and causes defects in TLR and IL1 ligand sensing. However, the mechanism by which IRAK4 activity regulates the production of downstream inflammatory cytokines is unclear. Using transcriptomic and biochemical analyses of human monocytes treated with a highly potent and selective inhibitor of IRAK4, we show that IRAK4 kinase activity controls the activation of interferon regulatory factor 5 (IRF5), a transcription factor implicated in the pathogenesis of multiple autoimmune diseases. Following TLR7/8 stimulation by its agonist R848, chemical inhibition of IRAK4 abolished IRF5 translocation to the nucleus and thus prevented IRF5 binding to and activation of the promoters of inflammatory cytokines in human monocytes. We also found that IKKß, an upstream IRF5 activator, is phosphorylated in response to the agonist-induced TLR signaling. Of note, IRAK4 inhibition blocked IKKß phosphorylation but did not block the nuclear translocation of NFκB, which was surprising, given the canonical role of IKKß in phosphorylating IκB to allow NFκB activation. Moreover, pharmacological inhibition of either IKKß or the serine/threonine protein kinase TAK1 in monocytes blocked TLR-induced cytokine production and IRF5 translocation to the nucleus, but not nuclear translocation of NFκB. Taken together, our data suggest a mechanism by which IRAK4 activity regulates TAK1 and IKKß activation, leading to the nuclear translocation of IRF5 and induction of inflammatory cytokines in human monocytes.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Monócitos / Modelos Imunológicos / Quinase I-kappa B / Fatores Reguladores de Interferon / Receptor 7 Toll-Like / Receptor 8 Toll-Like / Quinases Associadas a Receptores de Interleucina-1 Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Monócitos / Modelos Imunológicos / Quinase I-kappa B / Fatores Reguladores de Interferon / Receptor 7 Toll-Like / Receptor 8 Toll-Like / Quinases Associadas a Receptores de Interleucina-1 Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article