Activation of interleukin-2 gene transcription via the T-cell surface molecule CD28 is mediated through an NF-kB-like response element

C.L Verweij,M Geerts,L.A Aarden

doi:10.1016/s0021-9258(18)98663-1

C.L Verweij, M Geerts + Show 1 more

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https://doi.org/10.1016/s0021-9258(18)98663-1

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Abstract

Production of interleukin-2 (IL-2) by human T-lymphocytes can be augmented by costimulation via CD28. It has been reported that signaling via CD28 acts by stabilization of lymphokine mRNAs (Lindsten, T., June, C. H., Ledbetter, J. A., Stella, G., and Thompson, C. B. (1989) Science 244, 339-343). Here we demonstrate that costimulation via CD28 also provides a signal which activates transcription of the IL-2 gene A CD28-responsive element (CD28RE) in the IL-2 enhancer at position -162 to -152 was identified. This so far unidentified element shows sequence similarity to the kB enhancer motif. In vitro binding studies have demonstrated that the via CD28-induced signal synergizes with either phorbol myristate acetate or anti-CD3 for the induction of a nuclear factor that binds CD28RE and the human immunodeficiency virus (HIV-1) NF-kB motif. The significance of the sequence similarity of CD28RE with the kB enhancer motif was demonstrated by cross-competition studies using unlabeled CD28RE, HIV-1 NF-kB binding site, and a mutated version of the NF-kB motif. In addition, we found that NF-kB-dependent reporter gene expression was induced by costimulation via CD28. These results indicate that besides an effect on lymphokine mRNA stabilization, stimulation via CD28 acts at the level of transcription via coinduction of an NF-kB-like activity.

Highlights

From the Central Laboratoryof the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, Universityof Amsterdam, Amsterdam, The Netherlands implicated to control IL-2 production and T-lymphocyte activation
Hancer at position -162 to -152 was identified. This 2 gene is not transcribed in quiescent cells and neither antiso far unidentified element shows sequence similarity CD28 nor PMA alone induces detectable IL-2 gene transcripto the kB enhancer motif
CD28 Costimulatory Activationof IL-2 EnhancerActivityDisconnection of the IL-2 enhancer/promoter region from the IL-2 gene allows the analysis of transcriptional regulation of the IL-2 enhancerwithout interference of IL-2 mRNA stability effects

Summary

Introduction

From the Central Laboratoryof the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, Universityof Amsterdam, Amsterdam, The Netherlands implicated to control IL-2 production and T-lymphocyte activation. This 2 gene is not transcribed in quiescent cells and neither antiso far unidentified element shows sequence similarity CD28 nor PMA alone induces detectable IL-2 gene transcripto the kB enhancer motif. Gizes with either phorbol myristate acetate or antiCD3 for the induction of a nuclear factor that binds CD28RE and the human immunodeficiencyvirus (HIV1) NF-kB motif.

Results

Conclusion