IL-1 RECEPTOR AND TCR SIGNALS SYNERGIZE TO ACTIVATE NF-KAPPA-B-MEDIATED GENE-TRANSCRIPTION

Previous studies have demonstrated that IL-1 receptor(IL-1R)- and TCR- initiated signals can interact synergistically to increase the rate of transcription of several lymphokine and lymphokine receptor genes dur ing the competence phase of the activation program in T helper lymphoc ytes. In this report we describe how signals initiated through the typ e I IL-1R interact with signals from the antigen receptor to synergist ically augment the transactivating properties of NF-kappa B. The syner gistic antigen receptor initiated signals are mediated through protein kinase C because they can be mimicked by the phorbol ester, 12-O-tetr adecanoylphorbol-13-acetate, but not with calcium ionophores; and are staurosporine sensitive but cyclosporine resistant. Gel shift analyses demonstrate that NF-kappa B nuclear translocation is stimulated prima rily by IL-1 rather than by antigen receptor signals. Western blot and phosphorylation analyses demonstrate that the synergistic effect on N F-kappa B functional activity is independent of I kappa B alpha (MAD3) -NF-kappa B dissociation in the cytosol and is not associated with I k appa B nuclear translocation. The IL-1-induced NF-kappa B DNA nuclear localization is transient and can be prolonged either by an antigen re ceptor-initiated signal or by inhibiting protein synthesis. These resu lts suggest that IL-1 induces both NF-kappa B nuclear translocation an d the synthesis of a protein(s) responsible for terminating NF-kappa B -DNA interaction in the nucleus. Antigen receptor signals prolong NF-k appa B-DNA interaction, probably by functionally antagonizing the IL-1 -induced synthesis of a protein(s) responsible for the transient NF-ka ppa B-DNA interaction and consequently synergistically enhance IL-1-in duced NF-kappa B-dependent gene transcription.