title: Dual response to Fas ligation in human endothelial cells: apoptosis and induction of chemokines, interleukin-8 and monocyte chemoattractant protein-1.
abstract: BACKGROUND
  To maintain the integrity of tissues, endothelial cells play critical roles. Fas ligand (FasL) is well known to deliver a death signal through its receptor, Fas. The Fas/FasL system may concomitantly induce expressions of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) besides triggering apoptosis in endothelial cells. We also investigated whether an inhibitor of caspase-8 (Z-IETD-FMK) does modulate IL-8 and MCP-1 secretion.
  
  
  RESULTS
  After treatment with interferon-gamma (IFN-gamma), human recombinant FasL (hr FasL) or Fas agonistic antibody (CH-11) was added to cultured human endothelial cells. IFN-gamma up-regulated Fas mRNA levels. Fas ligation promoted apoptosis assessed by fluorescent-activated cell sorter (FACS) analysis in a dose-dependent manner and induced prominent DNA fragmentation. Simultaneously, IL-8 and MCP-1 were secreted from the endothelial cells in response to hr FasL or CH-11 in a dose-dependent manner (P < 0.01). Fas-neutralizing agent (Fas-Fc) suppressed the Fas-mediated secretions of IL-8 and MCP-1 (P < 0.01) both as well as the Fas-mediated apoptosis. On the other hand, whereas Z-IETD-FMK suppressed apoptosis, the inhibitor enhanced the Fas-mediated secretions of both IL-8 and MCP-1 beyond the value of the Fas stimulation alone (P < 0.01), suggesting an enhanced signalling for the chemokine expression.
  
  
  CONCLUSIONS
  In human endothelial cells, the Fas/FasL system induces both IL-8 and MCP-1 secretions probably via a caspase-8 independent pathway. The Fas/FasL system may amplify the inflammatory cascade in the vascular injury and atherogenesis by recruiting leukocytes at the region of apoptotic endothelial damage.
authors.affiliation: The First Department of Internal Medicine, Yamagata University School of Medicine, Japan. myamaokoa@med.kitasato-u.ac.jp
authors.forename: Minako
authors.initials: M
authors.lastname: Yamaoka-Tojo
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Joji
authors.initials: J
authors.lastname: Nitobe
authors.forename: Shuichi
authors.initials: S
authors.lastname: Abe
authors.forename: Sumito
authors.initials: S
authors.lastname: Inoue
authors.forename: Naoki
authors.initials: N
authors.lastname: Nozaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Okuyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Sata
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
authors.forename: Hidenori
authors.initials: H
authors.lastname: Nakamura
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D053938:DNA Fragmentation; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*
chemical_list: D018932:Chemokine CCL2; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D016209:Interleukin-8; D008562:Membrane Glycoproteins; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases