title: Leptospira santorosai Serovar Shermani detergent extract induces an increase in fibronectin production through a Toll-like receptor 2-mediated pathway.
abstract: Leptospirosis can activate inflammatory responses through Toll-like receptors (TLRs) and may cause renal tubulointerstitial fibrosis characterized by the accumulation of extracellular matrix (ECM). We have previously demonstrated that Leptospira santorosai serovar Shermani detergent extract stimulates ECM accumulation in vitro. The aim of this study was to examine the mechanistic basis of these previous observations and, in particular, to examine the potential involvement of TLRs. The addition of serovar Shermani detergent extract led to an increase in fibronectin gene expression and production. Inhibition of TLR2 but not TLR4 expression abrogated serovar Shermani detergent extract-mediated increases in fibronectin production. This response was also blocked by the knockdown of the gene expression of the TLR2 downstream transducers myeloid differentiation factor 88 (MyD88) and tumor necrosis factor receptor-associated factor 6 (TRAF6). Serovar Shermani detergent extract also activated nuclear factor-κB, and its inhibition by curcumin-attenuated serovar Shermani detergent extract induced increases in fibronectin production. These effects were also mimicked by the specific TLR2 agonist, Pam(3)CsK(4), a response that was also abrogated by the knockdown of MyD88 and TRAF6. Similarly, the administration of live leptospires to cells also induced fibronectin production that was blocked by inhibition of TLR2 and MyD88 expression. In conclusion, serovar Shermani detergent extract can induce fibronectin production through the TLR2-associated cascade, providing evidence of an association between TLRs and leptospirosis-mediated ECM deposition.
authors.affiliation: Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, 199 Tun-Hwa North Road, Taipei 105, Taiwan.
authors.forename: Ya-Chung
authors.initials: YC
authors.lastname: Tian
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Hung
authors.forename: Yi-Jung
authors.initials: YJ
authors.lastname: Li
authors.forename: Yung-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Chang
authors.forename: Tzung-Hai
authors.initials: TH
authors.lastname: Yen
authors.forename: Hsiang-Hao
authors.initials: HH
authors.lastname: Hsu
authors.forename: Mai-Szu
authors.initials: MS
authors.lastname: Wu
authors.forename: Aled
authors.initials: A
authors.lastname: Phillips
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Yang
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D045424:Complex Mixtures / Q000494:pharmacology*; D003902:Detergents; D024202:Electrophoretic Mobility Shift Assay; D005353:Fibronectins / Q000096:biosynthesis*; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007919:Leptospira / Q000737:chemistry / Q000378:metabolism*; D007922:Leptospirosis / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000187:drug effects / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D045424:Complex Mixtures; D003902:Detergents; D005353:Fibronectins; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; C495342:TLR2 protein, human; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2