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Increased Levels of NF-ATc2 Differentially Regulate CD154 and IL-2 Genes in T Cells from Patients with Systemic Lupus Erythematosus¹

Vasileios C. Kyttaris^*,,, Ying Wang^*,, Yuang-Taung Juang^*,, Arthur Weinstein and George C. Tsokos^2,*,

^* Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910; Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and Section of Rheumatology, Washington Hospital Center, Washington, DC 20010

T cells from patients with systemic lupus erythematosus (SLE) are characterized by heightened TCR-initiated free intracytoplasmic calcium responses. We demonstrate that activated T cells from SLE patients, but not from rheumatoid arthritis patients, displayed higher levels of the calcineurin-dependent transcription factor NF-ATc2 in the nucleus compared with control T cells. DNA NF-AT-binding activity was also increased, as was the amount of NF-ATc2 bound to the promoters of CD154 (CD40L) and IL-2 genes. Nevertheless, although high NF-ATc2 levels translated into higher CD154 transcription in SLE, IL-2 transcription was decreased. The absence of important transcriptional activators (AP-1, NF-B) and the presence of transcriptional repressors (cAMP response element modulator) on the IL-2 promoter explain this dichotomous effect.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by National Institutes of Health Grants RO1 AI42269 and RO1 AI49954. The opinions expressed herein are those of the authors and do not reflect those of the Department of Defense.

² Address correspondence and reprint requests to Dr. George C. Tsokos, Beth Israel Deacconess Medical Center, 4 Blackfan Circle. HIM-244, Boston, MA 02115. E-mail address: gtsokos{at}bidmc.harvard.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; ChIP, chromatin immunoprecipitation analysis; CREM, cAMP-responsive element modulator; hnRNP, heterogeneous nuclear ribonucleoprotein; RA, rheumatoid arthritis; SLEDAI, SLE disease activity index; GKLF, gut-enriched Kruppel-like factor.

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