Down-regulation of stromal cell-derived factor-1alpha-induced T cell chemotaxis by a peptide based on the complementarity-determining region 1 of an anti-DNA autoantibody via up-regulation of TGF-beta secretion.
Systemic lupus erythematosus (SLE) can be induced in mice by immunizing them with a monoclonal human anti-DNA Ab that expresses a major Id, designated 16/6Id. In addition, a peptide based on the sequence of the CDR 1 (hCDR1) of the 16/6Id ameliorated the clinical manifestations of SLE in experimental models. In this study we examined the effects of treating mice with human complementary-determining region 1 (hCDR1) on the subsequent chemotaxis of T cells derived from 16/6Id-primed mice. First we demonstrated elevated levels of stromal cell-derived factor-1alpha (SDF-1alpha) in the sera of SLE-afflicted mice and in the sera and lymphoid tissues of 16/6Id-immunized BALB/c mice shortly after the immunization. We then found that administration of hCDR1 to 16/6Id-immunized mice specifically down-regulated SDF1alpha-induced T cell chemotaxis through fibronectin and collagen type I. This was accompanied by diminished SDF1-alpha-induced T cell adhesion and ERK phosphorylation. Treatment with hCDR1 up-regulated TGF-beta secretion, which, in turn, inhibited the murine T cell adhesion to and chemotaxis through fibronectin as well as their ERK phosphorylation. Thus, the secretion of TGF-beta after treatment of 16/6Id-immunized mice with hCDR1 plays an important role in the down-regulation of SDF-1alpha-mediated T cell activation and the interactions with extracellular matrix moieties observed in the present study.
Sela
Uri
U
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Hershkoviz
Rami
R
Cahalon
Liora
L
Lider
Ofer
O
Mozes
Edna
E
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000276:immunology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000276:immunology* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D022801:Complementarity Determining Regions / Q000276:immunology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
D000974:Antibodies, Antinuclear; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D022801:Complementarity Determining Regions; C515256:Cxcl12 protein, mouse; D005353:Fibronectins; D010455:Peptides; D016212:Transforming Growth Factor beta