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NDT Advance Access originally published online on December 8, 2005
Nephrology Dialysis Transplantation 2006 21(4):898-910; doi:10.1093/ndt/gfi316
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Experimental Nephrology

Leptospiral membrane proteins stimulate pro-inflammatory chemokines secretion by renal tubule epithelial cells through toll-like receptor 2 and p38 mitogen activated protein kinase

Cheng-Chieh Hung1, Chiz-Tzung Chang1,2, Ya-Chung Tian1, Mai-Szu Wu1, Chun-Chen Yu1, Ming-Jeng Pan3, Alain Vandewalle4 and Chih-Wei Yang1

1 Kidney Institute and 2 Graduate Institute of Clinical Medical Science, Chang Gung Memorial Hospital, 3 Graduate Institute of Veterinary Medicine, National Taiwan University, Taipei, Taiwan and 4 Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 478, Faculty of Medicine Xavier Bichat, BP 416, 75870 Paris Cedex 18, France

Correspondence and offprint requests to: Chih-Wei Yang, Kidney Institute, Taipei, Taiwan Kidney Institute and Department of Nephrology, Chang Gung Memorial Hospital, 199, Tun-Hwa North Road, Taipei 105, Taiwan, Republic of China. Email: cwyang{at}ms1.hinet.net

Background. Leptospiral membrane proteins extracted from pathogenic Leptospira santarosai serovar Shermani (LMPS) stimulated pro-inflammatory chemokines production in cultured mouse proximal tubule epithelial cells (PTECs) and implicated its role in the pathogenesis of leptospira-induced tubulointerstitial nephritis. PTECs express the functional TLR2 and TLR4, which have been shown to play essential roles in innate immunity. This study investigated the roles of Toll-like receptors (TLRs) and mitogen-activated protein kinases (MAPKs) signalling pathways in the pathogenesis of leptospira-induced tubulointerstitial nephritis.

Methods. The immortalized mouse PKSV-PR late PTECs were used as the model system. The genes expression and secretion of CCL2/monocyte chemoattractant protein-1 (CCL2/MCP-1) and CXCL2/macrophage inflammatory protein-2 (CXCL2/MIP-2) were measured by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). We investigated MAPKs signalling pathways by Western blot and their reciprocal roles by specific inhibitors. A specific TLR2 neutralizing antibody was applied to evaluate the crosstalk between TLR2 and MAPKs.

Results. The LMPS stimulated extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinase (p38 MAPK), initiated the nuclear transcription factor kappaB (NF-{kappa}B), and enhanced the secretion of CCL2/MCP-1 and CXCL2/MIP-2. The LMPS also unregulated the level of TLR2 mRNA expression in PTECs through time- and dose-dependent effects. The LMPS enhanced the secretion of CCL2/MCP-1 and CXCL8/interleukin-8 (CXCL8/IL-8) in TLR-defective human embryonic kidney (HEK) 293 cells only when transfected with a TLR2 expressing plasmid. The secretions of CCL2/MCP-1 and CXCL2/MIP-2 stimulated by LMPS were significantly reduced by incubating PTECs with SB203580, an inhibitor of p38 MAPK. Furthermore, a neutralizing anti-mouse TLR2 antibody hindered the phosphorylation of p38 and LMPS-stimulated secretion of CCL2/MCP-1 and CXCL2/MIP-2.

Conclusion. These findings demonstrate that activation of p38 MAPK and release of chemokines by LMPS are mediated by TLR2 in renal proximal tubule cells. These results also implicate the crucial role of innate immunity in leptospira-induced tubulointerstitial nephritis.

Keywords: chemokines; leptospiral membrane proteins; mitogen-activated protein kinases; renal proximal tubule cells; receptor 2


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