Published ahead of print on March 17, 2004, doi:10.1164/rccm.200309-1329OC Am. J. Respir. Crit. Care Med., Volume 169, Number 10, May 2004, 1144-1151 A more recent version of this article appeared on May 15, 2004
Submitted on September 25, 2003 Monocyte Human Leukocyte Antigen-DR Transcriptional Downregulation by Cortisol During Septic ShockYves Le Tulzo1*,1 Service de Reanimation Medicale et des Maladies Infectieuses, Centre Hospitalier Universitaire de Rennes, Rennes, France; Laboratoire d'Hematologie et de Biologie des Cellules Sanguines UPRES-EA 22-33, Centre Hospitalier Universitaire de Rennes, Rennes, France, 2 Laboratoire d'Hematologie et de Biologie des Cellules Sanguines UPRES-EA 22-33, Centre Hospitalier Universitaire de Rennes, Rennes, France, 3 Laboratoire de Pharmacologie Clinique et Experimentale, Centre Hospitalier Universitaire de Rennes, Rennes, France, 4 Service de Reanimation Medicale et des Maladies Infectieuses, Centre Hospitalier Universitaire de Rennes, Rennes, France * To whom correspondence should be addressed. E-mail: yves.le-tulzo{at}univ-rennes1.fr.
Monocyte deactivation, has been identified as a major factor of immunosupression in sepsis and is associated to a loss of surface human leukocyte antigen (HLA)-DR expression on circulating monocytes. Using flow cytometry, quantitative RT-PCR, 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 (IL)-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 downmodulating its isoforms I and III. We conclude that in human sepsis, the loss of HLA-DR expression on circulating monocytes is associated with 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. Key words: Major histocompatibility complex type II, CIITA, immune paralysis, infection
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