Stat 6-dependent induction of myeloid derived suppressor cells after physical injury regulates nitric oxide response to endotoxin.
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.
Munera
Veronica
V
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Popovic
Petar J
PJ
Bryk
Jodie
J
Pribis
John
J
Caba
David
D
Matta
Benjamin M
BM
Zenati
Mazen
M
Ochoa
Juan B
JB
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*
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