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

Abstract

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-kappaB), 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.

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  • Authors+Show Affiliations

    ,

    Kidney Institute, Chang Gung Memorial Hospital, Taipei, Taiwan.

    , , , , , ,

    Source

    MeSH

    Animals
    Bacterial Outer Membrane Proteins
    Cells, Cultured
    Chemokine CCL2
    Chemokine CXCL2
    Chemokines
    Cytokines
    Enzyme-Linked Immunosorbent Assay
    Epithelial Cells
    Extracellular Signal-Regulated MAP Kinases
    Humans
    JNK Mitogen-Activated Protein Kinases
    Kidney Tubules, Proximal
    Leptospira
    Mice
    NF-kappa B
    RNA, Messenger
    Reverse Transcriptase Polymerase Chain Reaction
    Signal Transduction
    Toll-Like Receptor 2
    Transfection
    p38 Mitogen-Activated Protein Kinases

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    16339163

    Citation

    Hung, Cheng-Chieh, et al. "Leptospiral Membrane Proteins Stimulate Pro-inflammatory Chemokines Secretion By Renal Tubule Epithelial Cells Through Toll-like Receptor 2 and P38 Mitogen Activated Protein Kinase." Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association, vol. 21, no. 4, 2006, pp. 898-910.
    Hung CC, Chang CT, Tian YC, et al. Leptospiral membrane proteins stimulate pro-inflammatory chemokines secretion by renal tubule epithelial cells through toll-like receptor 2 and p38 mitogen activated protein kinase. Nephrol Dial Transplant. 2006;21(4):898-910.
    Hung, C. C., Chang, C. T., Tian, Y. C., Wu, M. S., Yu, C. C., Pan, M. J., ... Yang, C. W. (2006). Leptospiral membrane proteins stimulate pro-inflammatory chemokines secretion by renal tubule epithelial cells through toll-like receptor 2 and p38 mitogen activated protein kinase. Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association, 21(4), pp. 898-910.
    Hung CC, et al. Leptospiral Membrane Proteins Stimulate Pro-inflammatory Chemokines Secretion By Renal Tubule Epithelial Cells Through Toll-like Receptor 2 and P38 Mitogen Activated Protein Kinase. Nephrol Dial Transplant. 2006;21(4):898-910. PubMed PMID: 16339163.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Leptospiral membrane proteins stimulate pro-inflammatory chemokines secretion by renal tubule epithelial cells through toll-like receptor 2 and p38 mitogen activated protein kinase. AU - Hung,Cheng-Chieh, AU - Chang,Chiz-Tzung, AU - Tian,Ya-Chung, AU - Wu,Mai-Szu, AU - Yu,Chun-Chen, AU - Pan,Ming-Jeng, AU - Vandewalle,Alain, AU - Yang,Chih-Wei, Y1 - 2005/12/08/ PY - 2005/12/13/pubmed PY - 2006/9/27/medline PY - 2005/12/13/entrez SP - 898 EP - 910 JF - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association JO - Nephrol. Dial. Transplant. VL - 21 IS - 4 N2 - 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-kappaB), 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. SN - 0931-0509 UR - https://www.unboundmedicine.com/medline/citation/16339163/Leptospiral_membrane_proteins_stimulate_pro_inflammatory_chemokines_secretion_by_renal_tubule_epithelial_cells_through_toll_like_receptor_2_and_p38_mitogen_activated_protein_kinase_ L2 - https://academic.oup.com/ndt/article-lookup/doi/10.1093/ndt/gfi316 DB - PRIME DP - Unbound Medicine ER -