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.
Thomas
J A
JA
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235, USA. jthomas@hamon.swmed.edu
Allen
J L
JL
Tsen
M
M
Dubnicoff
T
T
Danao
J
J
Liao
X C
XC
Cao
Z
Z
Wasserman
S A
SA
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000502:physiology*; D005260:Female; D005298:Fertility / Q000235:genetics / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D053592:Interleukin-1 Receptor-Associated Kinases; D020382:Interleukin-18 / Q000502:physiology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D013234:Stem Cells; D016019:Survival Analysis
D016207:Cytokines; D007375:Interleukin-1; D020382:Interleukin-18; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases