title: Hydrocortisone prevents immunosuppression by interleukin-10+ natural killer cells after trauma-hemorrhage.
abstract: OBJECTIVE
  Trauma induces a state of immunosuppression, which is responsible for the development of nosocomial infections. Hydrocortisone reduces the rate of pneumonia in patients with trauma. Because alterations of dendritic cells and natural killer cells play a central role in trauma-induced immunosuppression, we investigated whether hydrocortisone modulates the dendritic cell/natural killer cell cross talk in the context of posttraumatic pneumonia.
  
  
  METHODS
  Experimental study.
  
  
  METHODS
  Research laboratory from an university hospital.
  
  
  METHODS
  Bagg Albino/cJ mice (weight, 20-24 g).
  
  
  METHODS
  First, in an a priori substudy of a multicenter, randomized, double-blind, placebo-controlled trial of hydrocortisone (200 mg/d for 7 d) in patients with severe trauma, we have measured the blood levels of five cytokines (tumor necrosis factor-α, interleukin-6, interleukin-10, interleukin-12, interleukin-17) at day 1 and day 8. In a second step, the effects of hydrocortisone on dendritic cell/natural killer cell cross talk were studied in a mouse model of posttraumatic pneumonia. Hydrocortisone (0.6 mg/mice i.p.) was administered immediately after hemorrhage. Twenty-four hours later, the mice were challenged with Staphylococcus aureus (7 × 10 colony-forming units).
  
  
  RESULTS
  Using sera collected during a multicenter study in patients with trauma, we found that hydrocortisone decreased the blood level of interleukin-10, a cytokine centrally involved in the regulation of dendritic cell/natural killer cell cluster. In a mouse model of trauma-hemorrhage-induced immunosuppression, splenic natural killer cells induced an interleukin-10-dependent elimination of splenic dendritic cell. Hydrocortisone treatment reduced this suppressive function of natural killer cells and increased survival of mice with posthemorrhage pneumonia. The reduction of the interleukin-10 level in natural killer cells by hydrocortisone was partially dependent on the up-regulation of glucocorticoid-induced tumor necrosis factor receptor-ligand (TNFsf18) on dendritic cell.
  
  
  CONCLUSIONS
  These data demonstrate that trauma-induced immunosuppression is characterized by an interleukin-10-dependent elimination of dendritic cell by natural killer cells and that hydrocortisone improves outcome by limiting this immunosuppressive feedback loop.
authors.affiliation: 1Faculty of Medicine, UPRES EA 3826, Thérapeutiques Cliniques et Expérimentales des Infections, University of Nantes, Nantes, France. 2Intensive Care Unit, Anesthesia and Critical Care Department, Hôtel Dieu-HME, University Hospital of Nantes, Nantes, France. 3Biochemistry Department, Hôtel Dieu-University Hospital of Nantes, Nantes, France. 4UMR PhAN 1280, Institut des Maladies de L'Appareil Digestif, University Hospital of Nantes, Nantes, France. 5CHU Nantes, Laboratoire d'Immunologie, Centre d'Immunomonitorage Nantes Atlantique (CIMNA), Nantes, France. 6INSERM Center of Research in Transplantation and Immunology UMR 1064, Nantes, France. 7INSERM, Unité 892, Institut de Recherche Thérapeutique, Université de Nantes, Nantes, France. 8Etablissement Français du Sang, Université de Nantes, Immunovirologie et Polymorphisme Génétique, Nantes, France. 9Department of Microbiology and Immunology [at the Doherty Institute of Infection and Immunity], The University of Australia, Parkville, Victoria, Australia. 10Department of Biochemistry and Molecular Biology at the Bio21 Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Antoine
authors.initials: A
authors.lastname: Roquilly
authors.forename: Alexis
authors.initials: A
authors.lastname: Broquet
authors.forename: Cédric
authors.initials: C
authors.lastname: Jacqueline
authors.forename: Damien
authors.initials: D
authors.lastname: Masson
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Segain
authors.forename: Cecile
authors.initials: C
authors.lastname: Braudeau
authors.forename: Mickael
authors.initials: M
authors.lastname: Vourc'h
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Caillon
authors.forename: Frédéric
authors.initials: F
authors.lastname: Altare
authors.forename: Regis
authors.initials: R
authors.lastname: Josien
authors.forename: Christelle
authors.initials: C
authors.lastname: Retière
authors.forename: Jose
authors.initials: J
authors.lastname: Villadangos
authors.forename: Karim
authors.initials: K
authors.lastname: Asehnoune
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003428:Cross Infection / Q000517:prevention & control; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D016753:Interleukin-10 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D018410:Pneumonia, Bacterial / Q000517:prevention & control; D013203:Staphylococcal Infections / Q000517:prevention & control; D015599:Trauma Severity Indices; D014947:Wounds and Injuries / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D016753:Interleukin-10; D006854:Hydrocortisone