Fas ligand exerts its pro-inflammatory effects via neutrophil recruitment but not activation.
Fas ligand (FasL) expression induces apoptosis of activated T cells and has been suggested as a strategy to inhibit graft rejection. Unfortunately, the use of FasL to confer 'immune privilege' in this setting has been hampered by the finding that it may also provoke a destructive granulocytic response. While the Fas/FasL-mediated apoptotic pathways are well defined, the pro-inflammatory effects of FasL are poorly understood. Our aim in this study was to define in vitro the biological effects of FasL on neutrophil recruitment and activation. DAP-3 cells expressing human FasL on the cell membrane (mFasL) potently induced apoptosis in human neutrophils and in activated T lymphocytes. Recombinant human soluble FasL (sFasL), by contrast, was a very weak inducer of apoptosis, even at high concentrations. This latter observation suggests that cleavage of mFasL by naturally occurring matrix metalloproteinases may serve to down-regulate FasL activity in vivo. However, in the presence of a cross-linking antibody, the efficiency of apoptosis-induction by sFasL was greatly increased, suggesting that the lesser pro-apoptotic potency of sFasL reflects an inability to induce trimerization of the Fas receptor. With regard to pro-inflammatory effects, we found that sFasL is a potent neutrophil chemoattractant and, given that it induces little apoptosis, the dominance of sFasL over mFasL may mean that graft-infiltrating neutrophils will survive to mediate inflammation. Neither sFasL nor mFasL produced neutrophil activation as assessed by chemiluminescence assay. This suggests that neutrophils recruited to an inflammatory site by FasL will be activated by mechanisms other than Fas-FasL signalling.
Dupont
Peter J
PJ
Department of Immunology, Hammersmith Hospital Campus, Imperial College London, London, United Kingdom.
Warrens
Anthony N
AN
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation; D053222:Fas Ligand Protein / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018375:Neutrophil Activation / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
D002630:Chemotactic Factors; D053222:Fas Ligand Protein; D011994:Recombinant Proteins