A tolerogenic peptide that induces suppressor of cytokine signaling (SOCS)-1 restores the aberrant control of IFN-gamma signaling in lupus-affected (NZB x NZW)F1 mice.
Interferon-gamma (IFN-gamma) plays a pathogenic role in systemic lupus erythematosus (SLE). Uncontrolled IFN-gamma signaling may result from a deficiency in the negative regulator, namely, suppressor of cytokine signaling-1 (SOCS-1). We investigated the activation status of IFN-gamma signaling pathway in SLE-afflicted (New-Zealand-BlackxNew-Zealand-White)F1 mice and determined its responsiveness when treating with a tolerogenic peptide, hCDR1, which ameliorates SLE. SOCS-1 was suppressed and pSTAT1 was enhanced in spleen-derived cells from SLE-affected mice as compared with healthy controls. Treatment with hCDR1 reversed the expression of these two molecules in association with clinical amelioration. In vitro stimulation with IFN-gamma resulted in elevated levels of SOCS-1 in cells from both vehicle and hCDR1-treated mice but this effect reached significance only in cells of the latter group, which also exhibited reduced levels of pSTAT1. Thus, SOCS-1 is diminished in SLE-affected mice, and treatment with hCDR1 results in its up-regulation thereby restoring control of IFN-gamma signaling pathway.
Sharabi
Amir
A
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Sthoeger
Zev M
ZM
Mahlab
Keren
K
Lapter
Smadar
S
Zinger
Heidy
H
Mozes
Edna
E
D000818:Animals; D001324:Autoantigens / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000628:therapy*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use; D050794:STAT1 Transcription Factor / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D001324:Autoantigens; C063762:CDR1 protein, human; D009419:Nerve Tissue Proteins; D010455:Peptides; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma