The role of apoptosis in the ameliorating effects of a CDR1-based peptide on lupus manifestations in a mouse model.
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-x(L). The ameliorative effects of hCDR1 were associated with down-regulation of caspase-8 and caspase-3, up-regulation of Bcl-x(L), 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-gamma and lowered the intensity of glomerular immune complex deposits and the levels of proteinuria. Furthermore, coincubation of Bcl-x(L) 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-gamma. Moreover, the Bcl-x(L)-expressing CD4(+)CD25(+) cells from hCDR1-treated mice induced the expression of Bcl-x(L) in CFSE-labeled CD4(+)CD25(-) cells of the SLE-afflicted mice. Thus, the reduction of apoptosis and the up-regulation of Bcl-x(L), which plays an apparent role in tolerance induction, contribute to at least part of the beneficial effects of hCDR1 on lupus manifestations.
Sharabi
Amir
A
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Luger
Dror
D
Ben-David
Hava
H
Dayan
Molly
M
Zinger
Heidey
H
Mozes
Edna
E
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D053148:Caspase 3 / Q000096:biosynthesis; D053181:Caspase 8 / Q000096:biosynthesis; D061945:Caspase Inhibitors; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010455:Peptides / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology; D051020:bcl-X Protein / Q000096:biosynthesis
D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; C483817:Cdr1 protein, mouse; D009419:Nerve Tissue Proteins; D010455:Peptides; D051020:bcl-X Protein; D053148:Caspase 3; D053181:Caspase 8