Basic Immunology and PathologyInhibition of p38 Mitogen-Activated Protein Kinase Is Effective in the Treatment of Experimental Crescentic Glomerulonephritis and Suppresses Monocyte Chemoattractant Protein-1 but Not IL-1β or IL-6Sheryanna, Abdulmunem*; Bhangal, Gurjeet*; McDaid, John*; Smith, Jennifer*; Manning, Anthony†; Foxwell, Brian M.J.‡; Feldmann, Marc‡; Cook, H. Terence§; Pusey, Charles D.*; Tam, Frederick W.K.* Author Information *Renal Section, Division of Medicine, ‡Kennedy Institute of Rheumatology, and §Department of Histopathology, Imperial College London, London, United Kingdom; and †Roche Palo Alto LLC, Palo Alto, California Address correspondence to: Dr. Frederick W.K. Tam, Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK. Phone: +44-20-8383-2354; Fax: +44-20-8383-2062; E-mail: [email protected] Accepted January 5, 2007 Received January 17, 2006 Journal of the American Society of Nephrology 18(4):p 1167-1179, April 2007. | DOI: 10.1681/ASN.2006010050 Buy Metrics Abstract Activation of p38 mitogen-activated protein kinase (MAPK) is known to be important in cytokine production and cell survival in inflammation. This study examined the effect of inhibiting p38 MAPK after onset of renal injury in an experimental model of crescentic glomerulonephritis. Furthermore, this study investigated whether p38 MAPK inhibition would cause widespread suppression of the cytokine network in vivo or uncontrolled apoptosis. In the in vivo studies, daily treatment with a p38 MAPKα/β inhibitor was started 1 h (early treatment study) or 4 d (late treatment study) after induction of nephrotoxic nephritis in Wistar Kyoto rats. The treated rats remained healthy with normal weight gain during the study. Both early and late treatment with p38 MAPK inhibitor reduced renal monocyte chemoattractant protein-1 (MCP-1) levels, the number of glomerular macrophages, the severity of tissue injury, and proteinuria compared with the vehicle group. Unexpected, treatment with p38 MAPK inhibitor did not suppress renal levels of IL-1β or IL-6. In the in vitro study, the p38 MAPKα/β inhibitor reduced production of MCP-1 and IL-6 by TNF-α–or IL-1β–stimulated mesangial cells without any effect on cell viability or apoptosis. In conclusion, p38 MAPK inhibition is effective in reducing the severity of crescentic glomerulonephritis even when treatment is started after onset of disease. The therapeutic effect is associated with selective suppression of MCP-1, without widespread suppression of cytokine production or increased apoptosis. Therefore, p38 MAPK therapeutic blockade is a promising strategy in the treatment of antibody-mediated glomerulonephritis. Copyright © 2007 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.