Regulation of Fas (APO-1, CD95) and Fas ligand expression in leukocytes during systemic inflammation in humans.
A potential role of Fas/FasL in sepsis is suggested by recent clinical studies showing that Fas and FasL could serve as markers for severity of sepsis. We sought to determine the effect of endotoxin infusion on expression of Fas and FasL. Healthy volunteers (n = 30) received 2 ng/kg endotoxin i.v. Endotoxin infusion decreased Fas expression on neutrophils and monocytes by 15-20% at 2-4 h in vivo and also in vitro. A rebound increase in Fas (30%) was seen on neutrophils at 24 h, and soluble FasL levels increased by 100% at 24 h. Fas mRNA levels increased 6-fold 4-6 h after endotoxin infusion as measured by real-time polymerase chain reaction. In contrast, FasL-mRNA levels in circulating leukocytes decreased by >80% 2h after lipopolysaccharide infusion. In summary, low-grade endotoxemia induces early down-modulation of Fas on leukocytes, followed by a several-fold increase in Fas-mRNA expression leading to later Fas surface upregulation on neutrophils. The upregulation of Fas expression, Fas mRNA, and later in FasL and sFas levels in endotoxemia replicates the increased fas levels found in septic patients.
Marsik
Claudia
C
Department of Clinical Pharmacology, Vienna University, Austria.
Halama
Thomas
T
Cardona
Francesco
F
Wlassits
Wilhelm
W
Mayr
Florian
F
Pleiner
Johannes
J
Jilma
Bernd
B
D000328:Adult; D017209:Apoptosis; D015536:Down-Regulation; D004731:Endotoxins / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D007375:Interleukin-1 / Q000097:blood; D007962:Leukocytes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018805:Sepsis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis*
D004731:Endotoxins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor