Fas (CD95) induces proinflammatory cytokine responses by human monocytes and monocyte-derived macrophages.
Fas (CD95, APO-1) is regarded as the prototypical cell death receptor of the TNFR superfamily. Fas-induced apoptosis is generally considered to be a noninflammatory process, contributing to the silent resolution of immune and inflammatory responses. However, accumulating evidence indicates that Fas may also induce cellular activation signals. We hypothesized that Fas could activate proinflammatory cytokine responses by normal human monocytes and macrophages. Monocytes were isolated by negative immunoselection from the PBMC fraction of venous blood from healthy volunteers, and monocyte-derived macrophages were cultivated in vitro. Both monocytes and monocyte-derived macrophages released TNF-alpha and IL-8 following Fas ligation, and conditioned medium from Fas-activated monocytes and macrophages induced the directed migration of neutrophils in a chemotaxis assay. Fas-induced monocyte cytokine responses were associated with monocyte apoptosis, nuclear translocation of NF-kappaB, and cytokine gene expression and were blocked by caspase inhibition but not by inhibition of IL-1beta signaling. In contrast, Fas-induced macrophage cytokine responses occurred in the absence of apoptosis and were caspase independent, indicating maturation-dependent differences in the Fas signaling pathways that lead to proinflammatory cytokine induction. Rather than contributing to the resolution of inflammation, Fas ligation on circulating monocytes and tissue macrophages may induce proinflammatory cytokine responses that can initiate acute inflammatory responses and tissue injury.
Park
David R
DR
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA. drp@u.washington.edu
Thomsen
Anni R
AR
Frevert
Charles W
CW
Pham
Uyenvy
U
Skerrett
Shawn J
SJ
Kiener
Peter A
PA
Liles
W Conrad
WC
D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism / Q000494:pharmacology*
D061945:Caspase Inhibitors; D016207:Cytokines; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D018836:Inflammation Mediators; D007375:Interleukin-1; D016209:Interleukin-8; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D019014:fas Receptor; D020169:Caspases