Role of interleukin-10 in the intracellular sequestration of human leukocyte antigen-DR in monocytes during septic shock.
Monocytes from many critically ill patients show a low level of major histocompatibility complex type II (MHC II) expression. This phenomenon is believed to play a role in these patients' increased susceptibility to secondary infections. In the present study, we show that the level of monocyte human leukocyte antigen (HLA)-DR expression inversely correlates with the degree of severity of the sepsis syndrome. The defect of the monocyte HLA-DR expression resides in an intracellular sequestration of the MHC II molecules, a posttranslational effect. No significant decrease in the rate of transcription of HLA-DR, or its major transcriptional inducer, Class II transactivator, was noted. The levels of HLA-DR protein produced by monocytes from patients with septic shock were comparable to those from healthy volunteers. Plasma from patients with septic shock induced significant HLA-DR endocytosis resulting in decreased surface HLA-DR expression of normal donor monocytes. This effect was partially blocked by anti-interleukin (IL)-10 monoclonal antibody, but not by antagonists to transforming growth factor-beta1, prostaglandins, or beta-adrenergic agonists. Altogether, these data suggest that HLA-DR molecules are re-endocytosed and retained intracellularly in monocytes from patients with septic shock, and that this phenomenon is partially mediated by IL-10. IL-10 may represent a future target for immunomodulating patients with the sepsis syndrome or critically ill patients at risk of developing infections.
Fumeaux
Thierry
T
Department of Internal Medicine, Division of Medical Intensive Care, and Faculty of Medicine, University Hospital of Geneva, Switzerland.
Pugin
Jérôme
J
D000328:Adult; D015153:Blotting, Western; D002403:Cathepsins / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006684:HLA-DR Antigens / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012772:Shock, Septic / Q000378:metabolism* / Q000503:physiopathology*; D014018:Tissue Distribution
D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; D016753:Interleukin-10; D002403:Cathepsins; C028217:cathepsin S