Enhanced indoleamine 2,3-dioxygenase activity in patients with severe sepsis and septic shock.
BACKGROUND
Severe sepsis results in a sustained deleterious immune dysregulation. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of tryptophan catabolism, plays a pivotal role in immune tolerance and is induced during various inflammatory conditions.


METHODS
Plasma samples obtained from patients with septic shock (n = 38), severe sepsis (n = 35), or sepsis (n = 10) and from healthy donors (n = 26) were analyzed for IDO activity by high-performance liquid chromatography. Lymphocyte, monocyte, and regulatory T cell counts as well as monocytic human leukocyte antigen DR (HLA-DR) expression were quantified by flow cytometry. Peripheral blood mononuclear cells and purified CD14(+) and CD14(-) fractions were assayed in vitro for spontaneous and inducible IDO expression and activity.


RESULTS
IDO activity gradually increased according to sepsis severity, and septic patients who died had higher IDO activity on admission than did survivors (P = .013). Monocytes were a major source of active IDO in normal peripheral blood. The percentage and absolute number of circulating CD14(+) cells were increased in septic patients, and their monocytes remained fully able to produce functional IDO after NF-kappaB-independent interferon gamma stimulation but not through NF-kappaB-dependent Toll-like receptor engagement.


CONCLUSIONS
IDO activity is increased during severe sepsis and septic shock and is associated with mortality. IDO production could be used to better characterize monocyte reprogramming in sepsis.
Tattevin
Pierre
P
Service des Maladies Infectieuses et Réanimation Médicale, CHU Pontchaillou, rue Henri le Guilloux, 35033 Rennes, France.
Monnier
Delphine
D
Tribut
Olivier
O
Dulong
Joelle
J
Bescher
Nadège
N
Mourcin
Frederic
F
Uhel
Fabrice
F
Le Tulzo
Yves
Y
Tarte
Karin
K
D000328:Adult; D000368:Aged; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005434:Flow Cytometry; D005602:France / Q000453:epidemiology; D006684:HLA-DR Antigens / Q000097:blood; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000097:blood*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology; D018805:Sepsis / Q000097:blood / Q000201:enzymology* / Q000401:mortality; D012772:Shock, Septic / Q000097:blood / Q000201:enzymology / Q000401:mortality; D050378:T-Lymphocytes, Regulatory; D055815:Young Adult
D006684:HLA-DR Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016328:NF-kappa B