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Departments of
*
Pediatrics and
Molecular Biology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75235; and
Tularik, Inc., South San Francisco, CA 94080
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-
B, 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-B when
stimulated with IL-1. Immune effector cells without IRAK exhibit a
defective IFN-
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.
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E. Vig, M. Green, Y. Liu, K.-Y. Yu, H.-J. Kwon, J. Tian, M. G. Goebl, and M. A. Harrington SIMPL Is a Tumor Necrosis Factor-specific Regulator of Nuclear Factor-kappa B Activity J. Biol. Chem., March 9, 2001; 276(11): 7859 - 7866. [Abstract] [Full Text] [PDF]
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J. C. M. Morel, C. C. Park, J. M. Woods, and A. E. Koch A Novel Role for Interleukin-18 in Adhesion Molecule Induction through NFkappa B and Phosphatidylinositol (PI) 3-Kinase-dependent Signal Transduction Pathways J. Biol. Chem., September 28, 2001; 276(40): 37069 - 37075. [Abstract] [Full Text] [PDF]
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L. Ling and D. V. Goeddel T6BP, a TRAF6-interacting protein involved in IL-1 signaling PNAS, August 15, 2000; 97(17): 9567 - 9572. [Abstract] [Full Text] [PDF]
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