Down-modulation of granulocyte macrophage-colony stimulating factor receptor on monocytes during human septic shock.
OBJECTIVE
Loss of surface human leukocyte antigen-DR (HLA-DR) on monocytes is a major factor of immunosuppression in sepsis. Granulocyte macrophage-colony stimulating factor (GM-CSF) up-regulates HLA-DR expression on monocytes via the GM-CSF receptor (GM-CSFr) through a transcriptional mechanism involving the class II transactivator factor (CIITA). We investigated monocyte GM-CSFr expression and its relationship with HLA-DR in septic patients.


METHODS
Prospective clinical experimental study.


METHODS
University hospital intensive care unit and research facility.


METHODS
Septic patients with and without septic shock, control patients.


METHODS
Flow cytometry and real-time quantitative reverse polymerase chain reaction were used to characterize GM-CSFr expression and transcription in septic patients and in ex vivo stimulated healthy monocytes.


RESULTS
We showed an early GM-CSFr down-modulation in patients with septic shock compared with those without septic shock and controls. A persistent low GM-CSFr expression was observed in patients who acquired secondary infections or in those who died, and this persistent defect correlated with severity scores. We demonstrated that GM-CSFr down-modulation occurs at a posttranscriptional level since we observed no alteration in GM-CSFr transcription in monocytes isolated from septic patients. Furthermore, we demonstrated that GM-CSFr expression levels on monocytes correlated not only with HLA-DR expression and transcription levels but also with RNA levels of its main transcriptional factor CIITA. Because we previously showed in septic patients a relationship between high cortisol plasma level and low monocyte HLA-DR expression, we investigated the effects of glucocorticoids on monocyte GM-CSFr expression and observed a similar posttranscriptional down-modulation of GM-CSFr by steroids. However, the in vivo putative role of steroids in HLA-DR down-regulation via GM-CSFr down-modulation needs further investigation.


CONCLUSIONS
Monocyte GM-CSFr down-modulation occurred in septic shock, was associated with severity, and might be either another manifestation of monocyte deactivation linked to sepsis or an additional mechanism participating in immunosuppression.
Département d'Hématologie, Immunologie et Thérapie Cellulaire, Hôpital Pontchaillou, Centre Hospitalier Universitaire, Rennes, France. celine.pangault@univ-rennes1.fr
Céline
C
Pangault
Yves
Y
Le Tulzo
Pierre
P
Tattevin
Valérie
V
Guilloux
Nadège
N
Bescher
Bernard
B
Drénou
D000328:Adult; D000368:Aged; D015536:Down-Regulation; D006801:Humans; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D011446:Prospective Studies; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D012772:Shock, Septic / Q000276:immunology*
D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor