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

Abstract

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.

Low monocyte HLA-DR expression as an indicator of immunodepression in very low birth weight infants

“…Therefore, in adults and VLBW infants, the molecular mechanisms might also have similarities. Internalization of HLA-DR molecules could be one mechanism for the rapid HLA-DR decline (21). In adults, IL-10 reduced HLA-DR expression by inhibiting exocytosis and the recycling of existing HLA-DR (22).…”

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

“…Antiinflammatory cytokines such as IL-10, IL-4, IL-13, and TGF-β and non-cytokine mediators, including prostaglandin E 2 , catecholamines, and glucocorticoids, have been detected in the serum of patients and/or experimental animals with sepsis (38)(39)(40)(41)(42). In particular, IL-10 appears to contribute to sepsis-induced inhibition of macrophage responses (10,21,43). In our study, however, we found a trend toward increased IL-10 production in IRAK-M -/-animals following CLP and i.t.…”

Immunoparalysis and Adverse Outcomes from Critical Illness

“…Mechanistic data from human subjects with immunoparalysis are rare, but Fumeaux et al demonstrated internalization of cell-surface HLA-DR molecules in normal human monocytes upon co-incubation with serum from septic patients [49]. This monocyte deactivation was partially reversed by the addition of anti-IL-10 neutralizing antibodies.…”

“…Numerous investigators have described reversal of endotoxin tolerance in vitro with agents including anti-IL-10 neutralizing antibody [49], IL-12 [67], GM-CSF [37,67,68], and flt3-ligand [69]. Hershman et al reported in 1989 that monocytes collected from immunoparalyzed adult trauma victims could be made to upregulate their HLA-DR expression upon ex vivo culture with the T H 1 cytokine IFNγ [70].…”