Lourenço Elaine V, Procaccini Claudio, Ferrera Francesca, Iikuni Noriko, Singh Ram P, Filaci Gilberto, Matarese Giuseppe, Shi Fu-Dong, Brahn Ernest, Hahn Bevra H, La Cava Antonio
Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
J Immunol. 2009 Jun 15;182(12):7415-21. doi: 10.4049/jimmunol.0804214.
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.
用基于抗DNA Ig的肽pConsensus治疗（NZB×NZW）F1（NZB/W）狼疮易感小鼠，可延长治疗动物的生存期，并有效延迟自身抗体和肾小球肾炎的出现。我们之前已经表明，这些保护作用部分与诱导抑制自身抗体反应的CD4⁺CD25⁺Foxp3⁺调节性T细胞（Tregs）有关。由于pConsensus的作用似乎继发于Tregs的定性而非定量变化，我们研究了Tregs中耐受性诱导的分子事件，发现包括ZAP70、p27、STAT1、STAT3、STAT6、SAPK、ERK和JNK在内的信号通路没有受到显著影响。然而，肽耐受影响了Tregs中MAPK p38的活性，其磷酸化因耐受而降低。用吡啶基咪唑抑制剂SB203580对未接触过抗原的NZB/W小鼠进行p38的药理学抑制，在体内重现了肽诱导耐受的效果，并保护小鼠免受狼疮样疾病的侵害。转移实验证实了p38在Tregs中对NZB/W小鼠疾病活动的作用。这些数据表明，狼疮Tregs中p38活性的调节可显著影响疾病活动。
