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J Biol Chem, Vol. 274, Issue 48, 34369-34374, November 26, 1999

Functional Disparity of Distinct CD28 Response Elements toward Mitogenic Responses

Azem Civil, Irma Rensink, Lucien A. Aarden, and Cornelis L. Verweij^§

From the  Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Department of Autoimmune Diseases, 1066 CX Amsterdam and ^§ Department of Rheumatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Activation of T cells through the antigen-specific T-cell receptor in combination with a costimulatory signal results in efficient cytokine gene transcription. The CD28-induced signal represents a major costimulatory signal for T cells. A CD28 response element, named CD28RE, was first identified in the interleukin-2 (IL-2) promoter region. Here we demonstrate that the NF-B sequence in the IL-6 promoter functions as a CD28 response element. Mutations in this sequence rendered the IL-6 promoter unresponsive to CD28 costimulation. Moreover, this element could replace the IL-2 CD28RE in conferring CD28 responsiveness to the IL-2 promoter. In analogy to the known CD28 response elements IL-2 CD28RE, IL-8 CD28RE, and the human immunodeficiency virus-1 (HIV-1) NF-B motif, the IL-6 NF-B motif efficiently bound c-Rel, c-Rel/NFKB1, and the recently identified inducible T-cell factor NF-MATp35. However, the IL-6 NF-B sequence together with the IL-8 CD28RE and HIV-1 NF-B sequence differed from the IL-2 CD28RE in the binding of NF-B/Rel family proteins. Although the IL-2 CD28RE exerted selective binding with c-Rel and c-Rel/NFKB1, the other CD28REs allowed efficient binding of a wide range of NF-B/Rel family proteins. The difference in binding specificity correlated with the capacity of the distinct CD28 response elements to function in the context of the IL-6 promoter in response to T-cell activation. Domain swapping experiments revealed that the IL-8 CD28RE and HIV-1 NF-B motif conferred similar responsiveness as the genuine IL-6 NF-B motif in the transcriptional activation of the IL-6 promoter upon CD28 costimulation. In contrast, replacement of the IL-6 NF-B sequence by the IL-2 CD28RE motif strongly reduced the responsiveness of the IL-6 promoter. These data indicate that despite the sequence similarity, two different classes of CD28 responsive elements exist that differ in their NF-B binding capacity and the ability to confer CD28 costimulatory responsiveness toward a heterologous promoter.

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