title: Tumor necrosis factor-α synergistically enhances polyinosinic-polycytidylic acid-induced toll-like receptor 3 signaling in cultured normal human mesangial cells: possible involvement in the pathogenesis of lupus nephritis.
abstract: OBJECTIVE
  It has been reported that tumor necrosis factor (TNF)-α plays dual controversial roles, beneficial or detrimental, in the pathogenesis of murine lupus nephritis (LN). However, its precise role in the development of human LN remains to be determined.
  
  
  METHODS
  We examine the effect of pretreatment with TNF-α on the toll-like receptor 3 (TLR3) signaling induced by polyinosinic-polycytidylic acid (poly IC), a synthetic analog of viral dsRNA that makes "pseudoviral" infection in cultured normal human mesangial cells, and analyzed the expression of CC chemokine ligand 5 (CCL5) via TLR3/interferon (IFN)-β/retinoic acid-inducible gene-I (RIG-I) pathway by reverse transcriptase-polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay.
  
  
  RESULTS
  We found synergistic effect of TNF-α, even at low level, on the expression of CCL5 induced by poly IC in a concentration-dependent manner, in comparison with that by poly IC alone. Knockdown of either IFN-β or RIG-I decreased CCL5 expression induced by TNF-α followed by poly IC.
  
  
  CONCLUSIONS
  Pretreatment with TNF-α leads marked activation of the TLR3/IFN-β/RIG-I/CCL5 axis induced by "pseudoviral" infection. Since chronic local activation of proinflammatory cytokines including TNF-α in resident renal cells may exist in patients with active lupus, synergistic effect of TNF-α and "pseudoviral" infection is possibly involved in the development of LN.
authors.affiliation: Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, 036-8562, Japan.
authors.forename: Tadaatsu
authors.initials: T
authors.lastname: Imaizumi
authors.forename: Tomomi
authors.initials: T
authors.lastname: Aizawa
authors.forename: Ryo
authors.initials: R
authors.lastname: Hayakari
authors.forename: Fei
authors.initials: F
authors.lastname: Xing
authors.forename: Pengfei
authors.initials: P
authors.lastname: Meng
authors.forename: Kazushi
authors.initials: K
authors.lastname: Tsuruga
authors.forename: Tomoh
authors.initials: T
authors.lastname: Matsumiya
authors.forename: Hidemi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tatsuta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000502:physiology; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000502:physiology*; D008181:Lupus Nephritis / Q000503:physiopathology*; D050527:Mesangial Cells / Q000187:drug effects*; D011070:Poly I-C / Q000494:pharmacology*; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000187:drug effects*; D051196:Toll-Like Receptor 3 / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018946:Chemokine CCL5; D016207:Cytokines; D011971:Receptors, Immunologic; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D011070:Poly I-C