Effects of overexpression of IL-1 receptor-associated kinase on NFkappaB activation, IL-2 production and stress-activated protein kinases in the murine T cell line EL4.
The association and activation of the IL-1 receptor-associated protein kinase (IRAK) to the IL-1 receptor complex is one of the earliest events detectable in IL-1 signal transduction. We generated permanent clones of the murine T cell line EL4 6.1 overexpressing human (h)IRAK to evaluate the role of this kinase in IL-1 signaling. Overexpression of hIRAK enhanced IL-1-stimulated activation of the transcription factor NFkappaB, whereas a truncated form (N-IRAK) specifically inhibited IL-1-dependent NFkappaB activity. In clones stably overexpressing hIRAK a weak constitutive activation of NFkappaB correlated with a low basal IL-2 production which was enhanced in an IL-1-dependent manner. Compared to the parental cell line the dose-response curve of IL-1-induced IL-2 production was shifted in both potency and efficacy. These results demonstrate that IRAK directly triggers NFkappaB-mediated gene expression in EL4 cells. Qualitatively different effects were observed for the IL-1-induced activation of stress-activated protein (SAP) kinases: permanent overexpression of IRAK did not affect the dose dependence but prolonged the kinetics of IL-1-induced activation of SAP kinases, suggesting that this signaling branch may be regulated by distinct mechanisms.
Knop
J
J
Institute of Molecular Pharmacology, Medical School Hannover, Germany.
Wesche
H
H
Lang
D
D
Martin
M U
MU
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D018076:DNA, Complementary; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases; D007376:Interleukin-2 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism*; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D017472:Receptors, Interleukin-1; D013601:T-Lymphocytes / Q000378:metabolism*; D014162:Transfection
D018076:DNA, Complementary; D007375:Interleukin-1; D007376:Interleukin-2; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases