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Modulation of p38 MAPK Activity in Regulatory T Cells after Tolerance with Anti-DNA Ig Peptide in (NZB x NZW)F₁ Lupus Mice¹

Elaine V. Lourenço^2,*, Claudio Procaccini^2,3,*, Francesca Ferrera^2,4,*, Noriko Iikuni^*, Ram P. Singh^*, Gilberto Filaci, Giuseppe Matarese, Fu-Dong Shi, Ernest Brahn^*, Bevra H. Hahn^* and Antonio La Cava^5,*

^* Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095; Department of Internal Medicine, University of Genoa, Italy; Immunology Laboratory, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Federico II University of Naples, Italy; and Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013

Treatment of (NZB x NZW)F₁ (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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grants AR53239 (to A.L.C.), AI065645 and AR054034 (to R.P.S.), AR42200 (to E.B.), AI46776 (to B.H.H.), the Arthritis Foundation Southern California Chapter (to A.L.C.), and the Arthritis National Research Foundation (to E.V.L.). G.M. is supported by the ERC-Starting Grant 202579 and by JDRF-Telethon Grant GJT08004.

² E.V.L., C.P., and F.F. contributed equally to this study.

³ Current address: Department of Biology and Cellular and Molecular Pathology, Federico II University of Naples, Italy.

⁴ Current address: Center of Excellence for Biomedical Research, University of Genoa, Italy.

⁵ Address correspondence and reprint requests to: Prof. Antonio La Cava, University of California, Los Angeles, 1000 Veteran Avenue 32–59, Los Angeles, CA 90095-1670. E-mail address: alacava{at}mednet.ucla.edu

⁶ Abbreviations used in this paper: Treg, CD4⁺CD25⁺Foxp3⁺ regulatory T cell; SLE, systemic lupus erythematosus; p-p38, phosphorylated p38; SAPK, stress-activated protein kinase; pCons, pConsensus.