IL-1 receptor and TCR signals synergize to activate NF-κB-mediated gene transcription

• Published in: International immunology 1995-01, Vol.7 (1), p.9-20
• Main Authors: McKean, David J., Bell, Michael, Huntoon, Catherine, Rastogi, Sanjeev, Van Norstrand, Michael, Podzorski, Ray, Nilson, Alan, Paya, Carlos
• Format: Article
• Language: English
• Subjects: Alkaloids - pharmacology; CD3 Complex - physiology; Cell Nucleus - metabolism; Cyclosporine - pharmacology; Cytoplasm - metabolism; DNA-Binding Proteins - metabolism; Gene Expression Regulation; Humans; IL-1; IL-2 gene transcription; In Vitro Techniques; Interleukin-1 - pharmacology; IκB; NF-kappa B - physiology; NK-κB; Protein Kinase C - physiology; Receptors, Antigen, T-Cell - physiology; Receptors, Interleukin-1 - physiology; RNA, Messenger - genetics; Signal Transduction; Staurosporine; T-Lymphocytes - physiology; Tetradecanoylphorbol Acetate - pharmacology; transcription factors; Transcription, Genetic; Transcriptional Activation; Tumor Cells, Cultured
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/7.1.9

Previous studies have demonstrated that IL-1 receptor (IL-1R) and TCR-initiated signals can interact synergisticaliy to increase the rate of transcription of several lymphokine and lymphokine receptor genes during the competence phase of the activation program in T helper lymphocytes. In this report we describe how signals Initiated through the type I IL-1R interact with signals from the antigen receptor to synergistlcally augment the transactivating properties of NF-κB. The synergistic antlgen receptor initlated signals are mediated through protein kinase C because they can be mimicked by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, but not with calcium ionophores; and are staurosporine sensitive but cyclosporine resistant. Gel shift analyses demonstrate that NF-κB nuclear translocation is stimulated primarily by IL-1 rather than by antigen receptor signals. Western blot and phosphorylation analyses demonstrate that the synerglstic effect on NF-κB functional activity is independent of IκBα (MAD3)–NF-κB dissociation in the cytosol and is not associated with IκB nuclear translocation. The IL-1-induced NF-κB DNA nuclear localization is transient and can be prolonged either by an antigen receptor-initiated signal or by inhibiting protein synthesis. These results suggest that IL-1 induces both NF-κB nuclear translocation and the synthesis of a protein(s) responsible for terminating NF-κB-DNA interaction in the nucleus. Antigen receptor signals prolong NF-κB-DNA interaction, probably by functionally antagonizing the IL-1-induced synthesis of a protein(s) responsible for the transient NF-κB-DNA interaction and consequently synergistically enhance IL-1-induced NF-κB-dependent gene transcription.