Modulation of p38 MAPK activity in regulatory T cells after tolerance with anti-DNA Ig peptide in (NZB x NZW)F1 lupus mice.
Treatment of (NZB x NZW)F(1) (NZB/W) lupus-prone mice with the anti-DNA Ig-based peptide pConsensus prolongs the survival of treated animals and effectively delays the appearance of autoantibodies and glomerulonephritis. We have previously shown that part of these protective effects associated with the induction of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) that suppressed autoantibody responses. Because the effects of pConsensus appeared secondary to qualitative rather than quantitative changes in Tregs, we investigated the molecular events induced by tolerance in Tregs and found that signaling pathways including ZAP70, p27, STAT1, STAT3, STAT6, SAPK, ERK, and JNK were not significantly affected. However, peptide tolerization affected in Tregs the activity of the MAPK p38, whose phosphorylation was reduced by tolerance. The pharmacologic inhibition of p38 with the pyridinyl imidazole inhibitor SB203580 in naive NZB/W mice reproduced in vivo the effects of peptide-induced tolerance and protected mice from lupus-like disease. Transfer experiments confirmed the role of p38 in Tregs on disease activity in the NZB/W mice. These data indicate that the modulation of p38 activity in lupus Tregs can significantly influence the disease activity.
Lourenço
Elaine V
EV
Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Procaccini
Claudio
C
Ferrera
Francesca
F
Iikuni
Noriko
N
Singh
Ram P
RP
Filaci
Gilberto
G
Matarese
Giuseppe
G
Shi
Fu-Dong
FD
Brahn
Ernest
E
Hahn
Bevra H
BH
La Cava
Antonio
A
D000818:Animals; D018791:CD4 Lymphocyte Count; D004247:DNA / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D007136:Immunoglobulins / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D051379:Mice; D010455:Peptides / Q000276:immunology* / Q000494:pharmacology; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D007136:Immunoglobulins; D010455:Peptides; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases