Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice

P Kanakaraj, K Ngo, Y Wu, A Angulo, P Ghazal, C A Harris, J J Siekierka, P A Peterson, W P Fung-Leung

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Interleukin (IL)-18 is functionally similar to IL-12 in mediating T helper cell type 1 (Th1) response and natural killer (NK) cell activity but is related to IL-1 in protein structure and signaling, including recruitment of IL-1 receptor-associated kinase (IRAK) to the receptor and activation of c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-kappaB. The role of IRAK in IL-18-induced responses was studied in IRAK-deficient mice. Significant defects in JNK induction and partial impairment in NF-kappaB activation were found in IRAK-deficient Th1 cells, resulting in a dramatic decrease in interferon (IFN)-gamma mRNA expression. In vivo Th1 response to Propionibacterium acnes and lipopolysaccharide in IFN-gamma production and induction of NK cytotoxicity by IL-18 were severely impaired in IRAK-deficient mice. IFN-gamma production by activated NK cells in an acute murine cytomegalovirus infection was significantly reduced despite normal induction of NK cytotoxicity. These results demonstrate that IRAK plays an important role in IL-18-induced signaling and function.
Original languageEnglish
Pages (from-to)1129-38
Number of pages10
JournalJournal of Experimental Medicine
Issue number7
Publication statusPublished - 1999


  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cell Differentiation
  • Cell Division
  • Chimera
  • Crosses, Genetic
  • Cytomegalovirus Infections
  • Cytotoxicity, Immunologic
  • Depression, Chemical
  • Enzyme Activation
  • Enzyme Induction
  • Female
  • Gene Expression Regulation
  • Interferon-gamma
  • Interleukin-1 Receptor-Associated Kinases
  • Interleukin-18
  • Interleukin-18 Receptor alpha Subunit
  • Interleukin-4
  • JNK Mitogen-Activated Protein Kinases
  • Killer Cells, Natural
  • Lipopolysaccharides
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases
  • NF-kappa B
  • Propionibacterium acnes
  • Protein Kinases
  • Receptors, Interleukin
  • Receptors, Interleukin-18
  • Signal Transduction
  • Th1 Cells
  • Th2 Cells


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