Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor–mediated immune responses but not in TCR signaling

Interleukin-1 receptor–associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)– and T cell receptor (TCR)–mediated signaling leading to the activation of nuclear factor κB (NF-κB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4 KN/KN mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4 KN/KN as well as IRAK-4 −/− macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1–dependent and –independent pathways were involved in early induction of NF-κB–regulated genes in response to TLR ligands such as tumor necrosis factor α and IκBζ. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927–1932), the TCR signaling was not impaired in IRAK-4 −/− and IRAK-4 KN/KN mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.

[1]  Takashi Saito,et al.  A Critical Role for the Innate Immune Signaling Molecule IRAK-4 in T Cell Activation , 2006, Science.

[2]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[3]  C. Sousa.  Faculty Opinions recommendation of Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses. , 2005 .

[4]  A. Al-ghonaium,et al.  Human TLR-7-, -8-, and -9-Mediated Induction of IFN-α/β and -λ Is IRAK-4 Dependent and Redundant for Protective Immunity to Viruses , 2005, Immunity.

[5]  D. Kuhns,et al.  Cutting Edge: Expression of IL-1 Receptor-Associated Kinase-4 (IRAK-4) Proteins with Mutations Identified in a Patient with Recurrent Bacterial Infections Alters Normal IRAK-4 Interaction with Components of the IL-1 Receptor Complex1 , 2005, The Journal of Immunology.

[6]  C. Coban,et al.  Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction , 2005, The Journal of experimental medicine.

[7]  K. Honda,et al.  Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[8]  C. Mirtsos,et al.  The Role of Interleukin 1 Receptor-associated Kinase-4 (IRAK-4) Kinase Activity in IRAK-4-mediated Signaling* , 2004, Journal of Biological Chemistry.

[9]  B. Beutler,et al.  Inferences, questions and possibilities in Toll-like receptor signalling , 2004, Nature.

[10]  J. Casanova,et al.  IRAK4 Kinase Activity Is Redundant for Interleukin-1 (IL-1) Receptor-associated Kinase Phosphorylation and IL-1 Responsiveness* , 2004, Journal of Biological Chemistry.

[11]  Zhijian J. Chen,et al.  The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. , 2004, Molecular cell.

[12]  U. Eriksson,et al.  IL-1R-Associated Kinase 4 Is Required for Lipopolysaccharide- Induced Activation of APC 1 , 2003, The Journal of Immunology.

[13]  S. Akira,et al.  Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway , 2003, Science.

[14]  S. Akira,et al.  The Roles of Toll-Like Receptor 9, MyD88, and DNA-Dependent Protein Kinase Catalytic Subunit in the Effects of Two Distinct CpG DNAs on Dendritic Cell Subsets1 , 2003, The Journal of Immunology.

[15]  Sophie Janssens,et al.  Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. , 2003, Molecular cell.

[16]  Charles A. Janeway,et al.  IRAK-M Is a Negative Regulator of Toll-like Receptor Signaling , 2002, Cell.

[17]  S. Akira,et al.  A variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MyD88-dependent and -independent pathways. , 2002, International immunology.

[18]  T. Mak,et al.  Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4 , 2002, Nature.

[19]  Holger Wesche,et al.  IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Dirk E. Smith,et al.  Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction , 2001, Nature.

[21]  S. Akira,et al.  Endotoxin-Induced Maturation of MyD88-Deficient Dendritic Cells1 , 2001, The Journal of Immunology.

[22]  S. Akira,et al.  A Toll-like receptor recognizes bacterial DNA , 2000, Nature.

[23]  P. Godowski,et al.  Toll-like receptor 2–mediated NF-κB activation requires a Rac1-dependent pathway , 2000, Nature Immunology.

[24]  S. Akira,et al.  Cutting Edge: Preferentially the R-Stereoisomer of the Mycoplasmal Lipopeptide Macrophage-Activating Lipopeptide-2 Activates Immune Cells Through a Toll-Like Receptor 2- and MyD88-Dependent Signaling Pathway1 , 2000, The Journal of Immunology.

[25]  S. Wasserman,et al.  Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. , 1999, Journal of immunology.

[26]  G. Stark,et al.  IRAK-M Is a Novel Member of the Pelle/Interleukin-1 Receptor-associated Kinase (IRAK) Family* , 1999, The Journal of Biological Chemistry.

[27]  S. Akira,et al.  Unresponsiveness of MyD88-deficient mice to endotoxin. , 1999, Immunity.

[28]  K. Burns,et al.  Overexpression of an enzymically inactive interleukin-1-receptor-associated kinase activates nuclear factor-kappaB. , 1999, The Biochemical journal.

[29]  J. Knop,et al.  Effects of IL‐1 receptor‐associated kinase (IRAK) expression on IL‐1 signaling are independent of its kinase activity , 1999, FEBS letters.

[30]  Crafford A. Harris,et al.  Interleukin (IL)-1 Receptor–associated Kinase (IRAK) Requirement for Optimal Induction of Multiple IL-1 Signaling Pathways and IL-6 Production , 1998, The Journal of experimental medicine.

[31]  Z. Cao,et al.  MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. , 1997, Immunity.

[32]  D. Goeddel,et al.  NF-κB Activation by Interleukin-1 (IL-1) Requires an IL-1 Receptor-associated Protein Kinase Activity (*) , 1995, The Journal of Biological Chemistry.

[33]  C. Janeway,et al.  Innate immune recognition. , 2002, Annual review of immunology.

[34]  P. Godowski,et al.  Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway. , 2000, Nature immunology.

[35]  D. Goeddel,et al.  NF-kappa B activation by interleukin-1 (IL-1) requires an IL-1 receptor-associated protein kinase activity. , 1995, The Journal of biological chemistry.