Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol during septic shock.
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.
Le Tulzo
Yves
Y
Service de Réanimation Médicale et des Maladies Infectieuses, Laboratoire d'Hématologie et de Biologie des Cellules Sanguines UPRES-EA 22-33, Centre Hospitalier Universitaire de Rennes, Rennes, France. yves.le-tulzo@univ-rennes1.fr
Pangault
Celine
C
Amiot
Laurence
L
Guilloux
Valérie
V
Tribut
Olivier
O
Arvieux
Cédric
C
Camus
Christophe
C
Fauchet
Renée
R
Thomas
Rémi
R
Drénou
Bernard
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015331:Cohort Studies; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use*; D007165:Immunosuppression Therapy; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D015999:Multivariate Analysis; D011336:Probability; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality; D015996:Survival Rate
D006684:HLA-DR Antigens; D006854:Hydrocortisone