The negative regulators Foxj1 and Foxo3a are up-regulated by a peptide that inhibits systemic lupus erythematosus-associated T cell responses

Uri Sela, Molly Dayan, Rami Hershkoviz, Liora Cahalon, Ofer Lider, Edna Mozes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

A peptide (hCDR1) based on the complementarity determining region-1 of an anti-DNA antibody ameliorates systemic lupus erythematosus (SLE) in induced and spontaneous lupus models. Our objectives were to determine the effects of hCDR1 on TCR signaling and on its negative regulators, Foxj1 and Foxo3a. BALB/c mice were immunized with the SLE-inducing anti-DNA antibody, designated 16/6Id, and treated with hCDR1. hCDR1 treatment specifically inhibited IFN-γ secretion by T cells in association with down-regulated T-bet expression and NF-ΚB activation; however, GATA-3 expression was not affected. Furthermore, TCR signaling (ZAP-70 phosphorylation) was inhibited, and the mRNA expression of the two modulators of Th1 activation, Foxj1 and Foxo3a, was significantly up-regulated. The latter were also elevated in SLE-afflicted (NZBxNZW)F1 mice that were treated with hCDR1. Addition of TGF-β, which was elevated following treatment with hCDR1, to T cells from 16/6Id immunized mice, up-regulated Foxj1 and Foxo3a mRNA expression, similarly to hCDR1. In contrast, anti-TGF-β antibodies added to hCDR1-treated T cells abrogated its effect. Thus, hCDR1 elevates TGF-β, which contributes to the up-regulation of T cell Foxj1 and Foxo3a expression, leading to inhibition of NF-ΚB activation and IFN-γ secretion, which is required for the maintenance of SLE.

Original languageEnglish
Pages (from-to)2971-2980
Number of pages10
JournalEuropean Journal of Immunology
Volume36
Issue number11
DOIs
StatePublished - Nov 2006

Keywords

  • Cytokines
  • Immunomodulatory peptide
  • Lupus
  • T cells
  • Transcription factors

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