IRAK1 Limits TLR3/4- and IFNAR-Driven IL-27 Production through a STAT1-Dependent Mechanism

Abstract

IL-27 is a cytokine exerting pleiotropic immunomodulatory effects on a broad spectrum of immune cells. Optimal IL-27 production downstream of TLR3/4 ligand stimulation relies on autocrine type I IFN signaling, defining a first and second phase in IL-27 production. This work shows that IL-1 receptor-associated kinase 1 (IRAK1) limits TLR3/4- and IFNAR-induced IL-27 production. At the mechanistic level, we identified IRAK1 as a novel regulator of STAT1, IRF1, and IRF9. We found hyperactivation of STAT1 together with increased nuclear levels of IRF1 and IRF9 in IRAK1-deficient murine macrophages compared with control cells following stimulation with LPS and poly(I:C). IRAK1-deficient human microglial cells showed higher basal levels of STAT1 and STAT2 compared with control cells. Blocking the kinase activity of TBK1/IKKε in IRAK1 knockdown human microglial cells reduced the high basal levels of STAT1/2, uncovering a TBK1/IKKε kinase-dependent mechanism controlling basal levels of STAT1/2. Stimulating IRAK1 knockdown human microglial cells with IFN-β led to increased IL-27p28 expression compared with control cells. In IRAK1-deficient murine macrophages, increased IL-27 levels were detected by ELISA following IFN-β stimulation compared with control macrophages together with increased nuclear levels of p-STAT1, IRF1, and IRF9. Treatment of wild-type and IRAK1-deficient murine macrophages with fludarabine similarly reduced TLR3/4-induced IL-27 cytokine levels. To our knowledge, this work represents the first report placing IRAK1 in the IFNAR pathway and identifies IRAK1 as an important regulator of STAT1, controlling IL-27 production downstream of TLR3/4 and IFNAR signaling pathways.

EGR3-HDAC6-IL-27 Axis Mediates Allergic Inflammation and Is Necessary for Tumorigenic Potential of Cancer Cells Enhanced by Allergic Inflammation-Promoted Cellular Interactions

“…IL-27, along with IFN-γ, can mediate virus-induced allergic airway inflammation ( 52 ). TLR3/4 and IFNAR signaling pathways are known to regulate the production of IL-27 ( 53 ). TLR4 activation by lipopolysaccharide (LPS) can increase the expression of IL-27 in macrophages ( 53 ).…”

“…TLR3/4 and IFNAR signaling pathways are known to regulate the production of IL-27 ( 53 ). TLR4 activation by lipopolysaccharide (LPS) can increase the expression of IL-27 in macrophages ( 53 ). IL-27 induces the activation of ERK and plays a pro-inflammatory role ( 54 ).…”

Interleukin Receptor Associated Kinase 1 Signaling and Its Association with Cardiovascular Diseases

“…IRAK1 also participates in STAT1 activation in IL-1R signaling [ 38 ]. In IRAK1-deficient macrophages, higher levels of STAT1/2 activities and IL27 production increase following IFN-β stimulation [ 39 ]. Since IL-10 and IL-27 are anti-inflammatory cytokines, IRAK1-mediated IL-1R to STAT signaling may play a role in the late stage tissue repair and remodeling, while IRAK1-mediated production of pro-inflammatory cytokines in NF-κB/MAPK signaling may engage in the early stage of infection and inflammation [ 35 , 36 ].…”

The immunomodulatory potentials of interleukin‐27 in airway allergies

“…The expression of EBI3 is triggered by signalling pathways such as TLR2/TLR4/TLR9‐MyD88‐NF‐KB/PU.1 11 . Of an important note, IRAK1 (IL‐1 receptor‐associated kinase 1) limits TLR3/4‐ and INFAR‐induced IL‐27 production by regulating the transcription factors (TFs) STAT1, IRF1 and IRF9 19 …”

“…11 Of an important note, IRAK1 (IL-1 receptor-associated kinase 1) limits TLR3/4-and INFAR-induced IL-27 production by regulating the transcription factors (TFs) STAT1, IRF1 and IRF9. 19 The IL-27 cellular effects are exerted through IL-27 receptor-an IL-27Rα [IL-27Rα or WSX1]-gp130 heterodimerexpressed on activated endothelial cells, mast cells, NK cells, monocytes, macrophages, DCs and naïve T cells. 10,12 The IL-27R signalling shows JAK-STAT isoform selectivity, and its operation is different in the context of the immune cells.…”