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Role of Interleukin-10 in the Intracellular Sequestration of Human Leukocyte Antigen-DR in Monocytes during Septic Shock

Departments of Internal Medicine, and Genetic and Microbiology, Division of Medical Intensive Care, and Faculty of Medicine, University Hospital of Geneva, Geneva, Switzerland

Correspondence and requests for reprints should be addressed to Jérôme Pugin, M.D., Division of Medical Intensive Care, University Hospital of Geneva, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. E-mail: pugin{at}cmu.unige.ch

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-ß₁, prostaglandins, or ß-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.

Key Words: human leukocyte antigen D • Class II transactivator protein • immune paralysis • major histocompatibility complex type II genes • antigen presentation

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