title: Stat 6-dependent induction of myeloid derived suppressor cells after physical injury regulates nitric oxide response to endotoxin.
abstract: OBJECTIVE
  To delineate the role of T-helper 2 (Th2) cytokines in the induction of trauma induced myeloid suppressor cells (TIMSC) and the regulation of nitric oxide production.
  
  
  BACKGROUND
  Trauma induces myeloid cells that express CD11b+/Gr1+ and arginase 1 and exhibit an immune suppressing activity. This article explores the mechanisms that induce TIMSC and the effects on nitric oxide production in response to endotoxin.
  
  
  METHODS
  TIMSC were studied in response to Th2 cytokines and a subsequent challenge to endotoxin. The role of Th2 cytokines was studied in STAT6-/- mice. Accumulation of TIMSC in spleens was studied using flow cytometry and immunhistochemistry. Plasma was recovered to measure accumulation of nitric oxide metabolites.
  
  
  RESULTS
  TIMSC accumulated in the spleen of injured mice and were particularly sensitive to IL-4 and IL-13 with large inductions of arginase activity. Significant blunting in both the accumulation of TIMSC in the spleen and induction of arginase 1 was observed in STAT6-/- mice after physical injury. Accumulation of nitric oxide metabolites to endotoxin was observed in STAT6-/- mice.
  
  
  CONCLUSIONS
  This study shows that induction of CD11b+/Gr1+ cells after physical injury play an essential role in the regulation of nitric oxide production after a septic challenge. The accumulation and induction of arginase 1 in TIMSC is Th2 cytokine dependent. To our knowledge, the role of TIMSC in the regulation of nitric oxide is a novel finding. This observation adds to the possibility that TIMSC could play an important role in immunosuppression observed after physical injury.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Munera
authors.forename: Petar J
authors.initials: PJ
authors.lastname: Popovic
authors.forename: Jodie
authors.initials: J
authors.lastname: Bryk
authors.forename: John
authors.initials: J
authors.lastname: Pribis
authors.forename: David
authors.initials: D
authors.lastname: Caba
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Matta
authors.forename: Mazen
authors.initials: M
authors.lastname: Zenati
authors.forename: Juan B
authors.initials: JB
authors.lastname: Ochoa
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D004731:Endotoxins / Q000494:pharmacology*; D004790:Enzyme Induction; D005434:Flow Cytometry; D007108:Immune Tolerance; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014947:Wounds and Injuries / Q000276:immunology*
chemical_list: D039481:CD11b Antigen; D004731:Endotoxins; C503133:Gr-1 protein, mouse; D018793:Interleukin-13; D019707:Receptors, Chemokine; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4; D009569:Nitric Oxide; D001119:Arginase