title: Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis.
abstract: Primary biliary cirrhosis (PBC) is characterized by chronic nonsuppurative destructive cholangitis (CNSDC) associated with destruction of small bile ducts. Although there have been significant advances in the dissection of the adaptive immune response against the mitochondrial autoantigens, there are increasing data that suggest a contribution of innate immune mechanisms in inducing chronic biliary pathology. We have taken advantage of our ability to isolate subpopulations of liver mononuclear cells (LMC) and examined herein the role of Toll-like receptors (TLRs), their ligands, and natural killer (NK) cells in modulating cytotoxic activity against biliary epithelial cells (BECs). In particular, we demonstrate that Toll-like receptor 4 ligand (TLR4-L)-stimulated NK cells destroy autologous BECs in the presence of interferon alpha (IFN-α) synthesized by TLR 3 ligand (TLR3-L)-stimulated monocytes (Mo). Indeed, IFN-α production by hepatic Mo is significantly increased in patients with PBC compared to disease controls. There were also marked increases in the cytotoxic activity of hepatic NK cells from PBC patients compared to NK cells from controls but only when the NK cells were prepared following ligation of both TLR3-L- and TLR4-L-stimulated LMC. These functional data are supported by the immunohistochemical observation of an increased presence of CD56-positive NK cells scattered around destroyed small bile ducts more frequently in liver tissues from PBC patients than controls.
  
  
  CONCLUSIONS
  These data highlight critical differences in the varied roles of Mo and NK cells following TLR3-L and TLR4-L stimulation.
authors.affiliation: Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. sshimoda@intmed1.med.kyushu-u.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimoda
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harada
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niiro
authors.forename: Ken
authors.initials: K
authors.lastname: Shirabe
authors.forename: Akinobu
authors.initials: A
authors.lastname: Taketomi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
authors.forename: Patrick
authors.initials: P
authors.lastname: Leung
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
mesh_terms: D001652:Bile Ducts / Q000276:immunology / Q000473:pathology*; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D011070:Poly I-C / Q000494:pharmacology; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D016898:Interferon-alpha; D008070:Lipopolysaccharides; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D011070:Poly I-C