EFFECTS OF OVEREXPRESSION OF IL-1 RECEPTOR-ASSOCIATED KINASE ON NF-KAPPA-B ACTIVATION, IL-2 PRODUCTION AND STRESS-ACTIVATED PROTEIN-KINASESIN 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 eve nts detectable in IL-1 signal transduction. We generated permanent clo nes 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 NF kappa B, whereas a truncated form (N-IRAK) specifically inhibited I L-1-dependent NF kappa B activity. In clones stably overexpressing hIR AK a weak constitutive activation of NF kappa B 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-ind uced IL-2 production was shifted in both potency and efficacy. These r esults demonstrate that IRAK directly triggers NF kappa B-mediated gen e expression in EL4 cells. Qualitatively different effects were observ ed for the IL-1-induced activation of stress-activated protein (SAP) k inases: permanent overexpression of IRAK did not affect the dose depen dence but prolonged the kinetics of IL-1-induced activation of SAP kin ases, suggesting that this signaling branch may be regulated by distin ct mechanisms.