Interleukin-1 receptor-associated kinase and TRAF-6 mediate the transcriptional regulation of interleukin-2 by interleukin-1 via NF kappa B but unlike interleukin-1 are unable to stabilise interleukin-2 mRNA

Interleukin-1 receptor-associated kinase, IRAK, has been shown to activate NF kappa B in response to interleukin-1. We have explored the involvement o f IRAK in regulation of the interleukin-2 gene in the murine thymoma cell l ine EL4.NOB-1 by examining its effect on interleukin-2 promoter-linked repo rter gene expression, interleukin-2 gene transcription and interleukin-2 pr otein production. Cells transfected with IRAK displayed high levels of phos phorylated IRAK, increased interleukin-2 promoter-linked reporter gene expr ession (which was dependent on NF kappa B) and interleukin-2 gene transcrip tion. IRAK was unable, however, to increase interleukin-2 protein productio n. Overexpression of TRAF-6 induced similar responses and again failed to i ncrease interleukin-2 protein production. A dominant negative TRAF-6 inhibi ted reporter gene expression and interleukin-2 protein production in respon se to both interleukin-1 and IRAK transfection. Interleukin-1 treatment and IRAK or TRAF-6 transfection increased interleukin-2 mRNA production. Only interleukin-1 treatment stabilised the induced transcripts with 50% being d etectable at 20 h post induction. The interleukin-2 mRNA induced in IRAK- o r TRAF-6-transfected cells was depleted by >90% at 6 h post induction. Thes e data implicate IRAK and TRAF-6 in transcriptional regulation of interleuk in-2 gene expression via NF kappa B, and provide direct evidence that IRAK lies upstream from TRAF-6. Neither IRAK nor TRAF-6 participates in stabilis ation of interleukin-2 mRNA which is required for interleukin-2 protein pro duction. (C) 1999 Elsevier Science B.V. All rights reserved.