title: Hepatic stellate cells secreting WFA+-M2BP: Its role in biological interactions with Kupffer cells.
abstract: OBJECTIVE
  Hepatic stellate cells (HSCs) play a central role in hepatic fibrosis and are regulated by Kupffer cells (KCs). Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) was recently identified as a serum marker for hepatic fibrosis. Although WFA+-M2BP was identified as a ligand of Mac-2, the function of WFA+-M2BP in hepatic fibrosis remains unclear.
  
  
  METHODS
  Liver specimens were obtained from five patients with cirrhosis, five with chronic hepatitis, and five without hepatic fibrosis. WFA+-M2BP kinetics were evaluated histologically and in subpopulations of liver cells such as HSCs, KCs, endothelial cells, biliary epithelial cells, and hepatocytes in in vitro culture. The function of WFA+-M2BP in activated HSCs was evaluated using immunoblot analysis.
  
  
  RESULTS
  Numbers of WFA+-M2BP-positive cells in liver tissues increased with fibrosis stage. There were significant differences in WFA+-M2BP levels between fibrosis stages F0 and F1-2 (P = 0.012) and between fibrosis stages F1-2 and F3-4 (P < 0.001). HSCs were the source of WFA+-M2BP secretion in in vitro cultures of liver cells, as determined by sandwich immunoassay. Cells of the human HSC line LX-2 also secreted WFA+-M2BP. Histologically, tissue sections showed that WFA+-M2BP was located in Mac-2-expressing KCs. In vitro assays showed that exogenous WFA+-M2BP stimulation enhanced Mac-2 expression in KCs and that HSCs co-cultured with KCs increased α-smooth muscle actin expression. Finally, Mac-2-depleted KCs with short interfering RNA had reduced α-smooth muscle actin expression following co-culturing with HSCs.
  
  
  CONCLUSIONS
  WFA+-M2BP from HSCs induces Mac-2 expression in KCs, which in turn activates HSCs to be fibrogenic.
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bekki
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yoshizumi
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimoda
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Itoh
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Harimoto
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Ikegami
authors.affiliation: Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuno
authors.affiliation: Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Narimatsu
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Shirabe
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D002450:Cell Communication; D002478:Cells, Cultured; D005355:Fibrosis / Q000235:genetics; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism*; D008024:Ligands; D008103:Liver Cirrhosis / Q000175:diagnosis* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D037121:Plant Lectins / Q000378:metabolism*; D034781:Receptors, N-Acetylglucosamine / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D008024:Ligands; D008562:Membrane Glycoproteins; D037121:Plant Lectins; D034781:Receptors, N-Acetylglucosamine; C114782:TAA90K protein, human; C040129:wisteria lectin
keywords: Kupffer cells; M2BPGi; Mac-2; WFA+-M2BP; hepatic stellate cells