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 RIS Download
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