TY - JOUR
T1 - The negative regulators Foxj1 and Foxo3a are up-regulated by a peptide that inhibits systemic lupus erythematosus-associated T cell responses
AU - Sela, Uri
AU - Dayan, Molly
AU - Hershkoviz, Rami
AU - Cahalon, Liora
AU - Lider, Ofer
AU - Mozes, Edna
PY - 2006/11
Y1 - 2006/11
N2 - 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.
AB - 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.
KW - Cytokines
KW - Immunomodulatory peptide
KW - Lupus
KW - T cells
KW - Transcription factors
UR - http://www.scopus.com/inward/record.url?scp=33751206845&partnerID=8YFLogxK
U2 - 10.1002/eji.200636137
DO - 10.1002/eji.200636137
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C2 - 17051618
AN - SCOPUS:33751206845
SN - 0014-2980
VL - 36
SP - 2971
EP - 2980
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 11
ER -