Monocyte Human Leukocyte Antigen–DR Transcriptional Downregulation by Cortisol during Septic Shock

Abstract

Monocyte deactivation has been identified as a major factor of immunosuppression in sepsis and is associated with a loss of surface human leukocyte antigen-DR (HLA-DR) expression on circulating monocytes. Using flow cytometry, quantitative reverse transcription-polymerase chain reaction, we investigated this phenomenon in septic patients. We confirmed the early loss of monocyte HLA-DR expression in all infected patients and demonstrated that this persistent lowered expression at Day 6 correlated with severity scores, secondary infection, and death. This phenomenon occurred at a transcriptional level via a decrease in the class II transactivator A (CIITA) transcription. Furthermore, these abnormalities correlated with the high cortisol levels observed in sepsis and not with those of other putative factors such as catecholamines or interleukin-10. Finally, in vitro studies evidenced that glucocorticoids decrease HLA-DR expression at a transcriptional level via a decrease in CIITA mRNA levels, mainly by down modulating its isoforms I and III. We conclude that in human sepsis, the loss of HLA-DR expression on circulating monocytes is associated with a poor outcome. We suggest that the high endogenous cortisol level observed in septic shock may be a possible new factor involved in the loss of HLA-DR expression on monocytes via its effect on HLA-DR and CIITA transcription.

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

“…Similar results have been reported in septic shock. Patients who developed secondary infections exhibited persistent decrease of mHLA-DR expression (68). Our unpublished data obtained from >200 septic shock patients indicate that, seven days after the onset of shock, patients with mHLA-DR <40% will later develop nosocomial infections.…”

“…There is also evidence for a direct interaction between nervous, endocrine, and immune systems. Numerous mediators participating in this network and increased during sepsis behave as immunosuppressors: cortisol, norepinephrine, acetylcholine (66)(67)(68)(69)(70). However, they all need to be assessed in large clinical studies.…”

Immunoparalysis and Adverse Outcomes from Critical Illness

“…Le Tulzo et al in 2004 studied 48 septic patients and found an association between high levels of circulating cortisol and reductions in monocyte HLA-DR expression on Day 6 of illness [53]. The authors then demonstrated in vitro that dexamethasone caused a down-regulation of a key transcription factor for HLA-DR in normal monocytes.…”

Reduced monocyte HLA-DR expression: A novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure

“…Reduced monocyte expression of the HLA class II DR molecule characterizes patients with septic shock with a poor prognosis, while recovery to normal is seen in those who survive. [16][17][18][19][20][21][22][23][24][25] The profound reduction in HLA-DR expression and a reduced ability in vitro to produce TNF-␣ following lipopolysaacharide stimulation is reflected in the fact that patients with septic shock usually succumb to repeated bacterial and opportunistic infections. 21 Recently, reduced monocyte HLA-DR expression has been reported in patients with septic decompensation of acute-on-chronic liver failure.…”