title: Toll-like receptor 3 signaling contributes to the expression of a neutrophil chemoattractant, CXCL1 in human mesangial cells.
abstract: BACKGROUND
  Mesangial proinflammatory chemokine/cytokine expressions via innate immunity play a pivotal role in the pathogenesis of glomerulonephritis. CXCL1/GROα is a strong neutrophil chemoattractant cytokine and reportedly plays an important role in regional inflammatory reactions. However, detailed signaling of mesangial CXCL1 expression induced by viral or "pseudoviral" immunity remains to be determined.
  
  
  METHODS
  We treated normal human mesangial cells (MCs) in culture with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, and analyzed the expression of CXCL1 by reverse transcription-polymerase chain reaction (RT-PCR), real-time quantitative RT-PCR and enzyme-linked immunosorbent assay. To elucidate the poly IC-induced signaling pathway for CXCL1 expression, we subjected the cells to RNA interference against Toll-like receptor (TLR) 3, retinoic acid-inducible gene-I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), interferon (IFN)-β, nuclear factor (NF)-κB p65 and IFN regulatory factor (IRF) 3. We also conducted an immunofluorescence study to examine mesangial CXCL1 expression in biopsy specimens from patients with lupus nephritis (LN) and IgA nephropathy (IgAN).
  
  
  RESULTS
  We found that activation of TLR3 signaling could induce the expression of CXCL1 in MCs. NF-κB, IRF3 and IFN-β, but neither RIG-I nor MDA5, were found to be involved in mesangial CXCL1 expression in this setting. Induction of CXCL1 by poly IC was inhibited by pretreatment of cells with dexamethasone. Intense glomerular CXCL1 expression was observed in biopsy specimens from patients with LN, whereas only a trace staining occurred in specimens from patients with IgAN.
  
  
  CONCLUSIONS
  TLR3 signaling also contributes to the CXCL1 expression in MCs. These observations further support the implication of viral and "pseudoviral" immunity in the pathogenesis of inflammatory renal diseases, especially in LN.
authors.affiliation: Department of Vascular Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
authors.forename: Tadaatsu
authors.initials: T
authors.lastname: Imaizumi
authors.affiliation: Department of Pediatrics, Hirosaki University Hospital, 53 Hon-cho, Hirosaki, 036-8563, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Aizawa
authors.affiliation: Department of Vascular Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Segawa
authors.affiliation: Department of Cardiology, Respiratory Medicine and Nephrology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Department of Pediatrics, Hirosaki University Hospital, 53 Hon-cho, Hirosaki, 036-8563, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Tsuruga
authors.affiliation: Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Kawaguchi
authors.affiliation: Department of Vascular Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
authors.forename: Tomoh
authors.initials: T
authors.lastname: Matsumiya
authors.affiliation: Department of Vascular Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Joh
authors.affiliation: Department of Pediatrics, Hirosaki University Hospital, 53 Hon-cho, Hirosaki, 036-8563, Japan. hirotana@cc.hirosaki-u.ac.jp.|Department of School Health Science, Faculty of Education, Hirosaki University, 1 Bunkyo-cho, Hirosaki, 036-8560, Japan. hirotana@cc.hirosaki-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000096:biosynthesis* / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D005922:Glomerulonephritis, IGA / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D008181:Lupus Nephritis / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D003907:Dexamethasone; D011070:Poly I-C
keywords: CXCL1; Human mesangial cells; IFN-β; Inflammatory renal diseases; Lupus nephritis; Psuedoviral immunity; TLR3