title: Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity.
abstract: Signaling through the Fas/Fas ligand (FasL) pathway plays a central role in immune-cell response and function; however, under certain pathological conditions such as sepsis, it may contribute to the animal's or patient's morbidity and mortality. To determine the contribution of FasL to mortality, we conducted survival studies by blocking Fas/FasL with Fas receptor fusion protein (FasFP) in vivo. C3H/HeN mice received FasFP or the saline vehicle (veh) immediately (0 h) or delayed (12 h), after sepsis induced by cecal ligation and puncture (CLP). Subsequently, we examined the effect of FasFP treatment (12 h post-CLP) on macrophage apoptosis and functional capacities. Peritoneal and splenic macrophages and Kupffer cells from sham-veh-, CLP-veh-, sham-FasFP-, or CLP-FasFP-treated mice were harvested 24 h after CLP and stimulated with lipopolysaccharide (LPS) for 24 h. The results indicate that only delayed (12 h) but not 0 h administration of FasFP demonstrated a significant increase in survival. The ability of all macrophage populations to release interleukin (IL)-6 was significantly depressed, and IL-10 release was augmented after CLP. FasFP treatment attenuated the increased IL-10 release in Kupffer cells. However, althogh enhanced susceptibility to LPS-induced apoptosis could be suppressed in CLP mouse Kupffer cells by FasFP, FasFP did not change the peritoneal or splenic macrophage response. Furthermore, FasFP attenuated the elevated plasma levels of liver enzymes after sepsis. These data indicate that in vivo inhibition of Fas/FasL signaling has tissue-specific effects on the induction of macrophage apoptosis, functional changes, and liver damage, which may contribute to the host's ability to ward off a septic challenge.
authors.affiliation: Brown University School of Medicine and Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Chun-Shiang
authors.initials: CS
authors.lastname: Chung
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Song
authors.forename: Joanne
authors.initials: J
authors.lastname: Lomas
authors.forename: H Hank
authors.initials: HH
authors.lastname: Simms
authors.forename: Irshad H
authors.initials: IH
authors.lastname: Chaudry
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
mesh_terms: D000818:Animals; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000097:blood; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002432:Cecum / Q000293:injuries; D002478:Cells, Cultured; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D009336:Necrosis; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D018805:Sepsis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013154:Spleen / Q000166:cytology; D015996:Survival Rate; D019014:fas Receptor / Q000502:physiology*
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D015850:Interleukin-6; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D016753:Interleukin-10; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases