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A Peptide That Ameliorates Lupus Up-Regulates the Diminished Expression of Early Growth Response Factors 2 and 3¹

Uri Sela^*,, Molly Dayan^*, Rami Hershkoviz, Ofer Lider^2,* and Edna Mozes^3,*

^* Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; and Assaf-Harofeh Medical Center and the Sakler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Expansion of autoreactive T cells and their resistance to anergy was demonstrated in systemic lupus erythematosus (SLE). A pair of transcription factors, early growth response 2 (Egr-2) and 3 (Egr-3), are negative regulators of T cell activation that were shown to be important in anergy. A peptide (designated hCDR1 for human CDR1) based on the CDR-1 of an anti-DNA Ab ameliorated SLE in both induced and spontaneous lupus models. Our objectives were to determine the expression levels of Egr-2 and Egr-3 in autoreactive T cells following immunization with the lupus-inducing anti-DNA Ab that bears a common Id designated 16/6Id and also in a full-blown SLE and to determine the effect of hCDR1 on these transcription factors. We demonstrated diminished expression levels of Egr-2 and Egr-3 mRNA both early after immunization with the 16/6Id and in SLE-afflicted (NZB x NZW)F1 (New Zealand Black and New Zealand White) mice. Furthermore, by down-regulating Akt phosphorylation and up-regulating TGFβ secretion, treatment with hCDR1 significantly up-regulated Egr-2 and Egr-3 expression. This was associated with an increased expression of the E3 ligase Cbl-b. Inhibition of Akt in T cells of immunized mice decreased, whereas silencing of the Egr-2 and Egr-3 in T cells of hCDR1-treated mice increased IFN- secretion. Thus, hCDR1 down-regulates Akt phosphorylation, which leads to up-regulated expression of T cell Egr-2 and Egr-3, resulting in the inhibition of IFN- secretion that is required for the maintenance of SLE.

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 study was supported by Teva Pharmaceutical Industries (to E.M.).

² O.L. is deceased.

³ Address correspondence and reprint requests to Dr. Edna Mozes, Department of Immunology, The Weizmann Institute of Science, P.O. Box 26, Rehovot 76100, Israel. E-mail address: edna.mozes{at}weizmann.ac.il

⁴ Abbreviations used in this paper: Egr, early growth response; hCDR1, human CDR1; hIgG, human IgG; LFA-1, leukocyte function Ag 1; LN, lymph node; NZB/W, (NZB x NZW)F1 (New Zealand Black and New Zealand White); p-Akt, phosphorylated Akt; siRNA, small interfering RNA; SLE, systemic lupus erythematosus.

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