TY - JOUR
T1 - The role of apoptosis in the ameliorating effects of a CDR1-based peptide on lupus manifestations in a mouse model
AU - Sharabi, Amir
AU - Luger, Dror
AU - Ben-David, Hava
AU - Dayan, Molly
AU - Zinger, Heidey
AU - Mozes, Edna
PY - 2007/10/15
Y1 - 2007/10/15
N2 - Experimental systemic lupus erythematosus (SLE) can be induced in mice following immunization with an anti-DNA mAb expressing a major Id, 16/6Id. Treatment with a peptide, designated human CDR1 (hCDR1; Edratide), that is based on the sequence of CDR1 of the 16/6Id ameliorated disease manifestations. In the present study, we investigated the roles of apoptosis and related molecules in BALB/c mice with induced experimental SLE following treatment with hCDR1. A higher state of activation and increased rate of apoptosis were found in lymphocytes of SLE-afflicted mice as compared with healthy controls. The latter effects were associated with up-regulated caspase-8 and caspase-3, and down-regulated Bcl-xL. The ameliorative effects of hCDR1 were associated with down-regulation of caspase-8 and caspase-3, up-regulation of Bcl-xL, and a reduced rate of apoptosis. Treatment of diseased mice with an apoptosis-reducing compound that inhibited caspases down-regulated the secretion of the pathogenic cytokine IFN-γ and lowered the intensity of glomerular immune complex deposits and the levels of proteinuria. Furthermore, coincubation of Bcl-xL inhibitors with hCDR1-treated cells abrogated the ability of hCDR1 to reduce the activation state of lymphocytes and to down-regulate the secretion of IL-10 and IFN-γ. Moreover, the Bcl-x L-expressing CD4+CD25+ cells from hCDR1-treated mice induced the expression of Bcl-xL in CFSE-labeled CD4 +CD25- cells of the SLE-afflicted mice. Thus, the reduction of apoptosis and the up-regulation of Bcl-xL, which plays an apparent role in tolerance induction, contribute to at least part of the beneficial effects of hCDR1 on lupus manifestations.
AB - Experimental systemic lupus erythematosus (SLE) can be induced in mice following immunization with an anti-DNA mAb expressing a major Id, 16/6Id. Treatment with a peptide, designated human CDR1 (hCDR1; Edratide), that is based on the sequence of CDR1 of the 16/6Id ameliorated disease manifestations. In the present study, we investigated the roles of apoptosis and related molecules in BALB/c mice with induced experimental SLE following treatment with hCDR1. A higher state of activation and increased rate of apoptosis were found in lymphocytes of SLE-afflicted mice as compared with healthy controls. The latter effects were associated with up-regulated caspase-8 and caspase-3, and down-regulated Bcl-xL. The ameliorative effects of hCDR1 were associated with down-regulation of caspase-8 and caspase-3, up-regulation of Bcl-xL, and a reduced rate of apoptosis. Treatment of diseased mice with an apoptosis-reducing compound that inhibited caspases down-regulated the secretion of the pathogenic cytokine IFN-γ and lowered the intensity of glomerular immune complex deposits and the levels of proteinuria. Furthermore, coincubation of Bcl-xL inhibitors with hCDR1-treated cells abrogated the ability of hCDR1 to reduce the activation state of lymphocytes and to down-regulate the secretion of IL-10 and IFN-γ. Moreover, the Bcl-x L-expressing CD4+CD25+ cells from hCDR1-treated mice induced the expression of Bcl-xL in CFSE-labeled CD4 +CD25- cells of the SLE-afflicted mice. Thus, the reduction of apoptosis and the up-regulation of Bcl-xL, which plays an apparent role in tolerance induction, contribute to at least part of the beneficial effects of hCDR1 on lupus manifestations.
UR - http://www.scopus.com/inward/record.url?scp=38449119975&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.179.8.4979
DO - 10.4049/jimmunol.179.8.4979
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C2 - 17911582
AN - SCOPUS:38449119975
SN - 0022-1767
VL - 179
SP - 4979
EP - 4987
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -
