A peptide that ameliorates lupus up-regulates the diminished expression of early growth response factors 2 and 3.
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 TGFbeta 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-gamma 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-gamma secretion that is required for the maintenance of SLE.
Sela
Uri
U
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Dayan
Molly
M
Hershkoviz
Rami
R
Lider
Ofer
O
Mozes
Edna
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017635:Clonal Anergy / Q000187:drug effects*; D051767:Early Growth Response Protein 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051776:Early Growth Response Protein 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D010446:Peptide Fragments / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D051767:Early Growth Response Protein 2; D007376:Interleukin-2; D010446:Peptide Fragments; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D051776:Early Growth Response Protein 3; C516151:edratide; D007371:Interferon-gamma; D050721:Proto-Oncogene Proteins c-cbl; D051057:Proto-Oncogene Proteins c-akt