IL-10 induces apoptosis in human monocytes involving the CD95 receptor/ligand pathway.
The cytokine IL-10 exerts potent immunosuppressive and anti-inflammatory effects, although the mechanisms of this action remain largely unknown. In the present study, we investigated the effects of IL-10 in human peripheral blood monocytes. We were able to demonstrate that IL-10 dose- and time-dependently triggers apoptosis in these cells as detected by annexin-V staining, the nick end labeling (TUNEL) procedure, electron microscopy and analysis of DNA laddering. IL-10-induced apoptosis required the activation of proteases of the caspase family, since a peptide caspase inhibitor attenuated cell death and, in addition, the proteolytic activation of caspase-8 was observed. Since caspase-8 has been implicated as a regulator of apoptosis mediated by death receptors, we investigated a potential involvement of the CD95 receptor/ligand system. Indeed, treatment of monocytes with IL-10 induced a dose-dependent up-regulation of CD95 receptor and ligand expression on the monocyte surface. Furthermore, a CD95 ligand-neutralizing antibody significantly inhibited IL-10-induced apoptosis. In summary, our data show that IL-10 triggers monocyte apoptosis involving the CD95 system via an autocrine or paracrine process. Therefore, at least part of the anti-inflammatory properties of IL-10 may involve induction of apoptosis in monocytes.
Schmidt
M
M
Department of Medicine, University of Münster, Germany.
Lügering
N
N
Pauels
H G
HG
Schulze-Osthoff
K
K
Domschke
W
W
Kucharzik
T
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism* / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D016753:Interleukin-10; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases