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Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase.

Stimulation of the type 1 IL-1R (IL-1R1) and the IL-18R by their cognate ligands induces recruitment of the IL-1R-associated kinase (IRAK). Activation of IRAK leads in turn to nuclear translocation of NF-kappaB, which directs expression of innate and adaptive immune response genes. To study IRAK function in cytokine signaling, we generated cells and mice lacking the IRAK protein. IRAK-deficient fibroblasts show diminished activation of NF-kappaB when stimulated with IL-1. Immune effector cells without IRAK exhibit a defective IFN-gamma response to costimulation with IL-18. Furthermore, mice lacking the Irak gene demonstrate an attenuated response to injected IL-1. Deletion of Irak, however, does not affect the ability of mice to develop delayed-type hypersensitivity or clear infection with the intracellular parasite, Listeria monocytogenes. These results demonstrate that although IRAK participates in IL-1 and IL-18 signal transduction, residual cytokine responsiveness operates through an IRAK-independent pathway.

Pubmed ID: 10395695


  • Thomas JA
  • Allen JL
  • Tsen M
  • Dubnicoff T
  • Danao J
  • Liao XC
  • Cao Z
  • Wasserman SA


Journal of immunology (Baltimore, Md. : 1950)

Publication Data

July 15, 1999

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01 GM50545

Mesh Terms

  • Animals
  • Cell Line
  • Cytokines
  • Female
  • Fertility
  • Hypersensitivity, Delayed
  • Immunologic Deficiency Syndromes
  • Interleukin-1
  • Interleukin-1 Receptor-Associated Kinases
  • Interleukin-18
  • Listeriosis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B
  • Protein Kinases
  • Receptors, Interleukin-1
  • Sequence Deletion
  • Signal Transduction
  • Spleen
  • Stem Cells
  • Survival Analysis