Elevated expression of cyclooxygenase-2 contributes to immune dysfunction in a murine model of trauma.
BACKGROUND
Cyclooxygenase-2 (Cox-2), the inducible form of Cox, is a rate-limiting enzyme in the synthesis of prostaglandins (PGs). Prostaglandin E2 (PGE2) and other eicosanoids possess immunosuppressive properties. Previously, traumatic injury was found to stimulate the synthesis of PGs and cause immune dysfunction. In this study a murine model was used to determine the effect of trauma on the expression of Cox-2 in macrophages and to elucidate the role of Cox-2 in trauma-induced immune dysfunction.


METHODS
Mice were randomized to control or trauma (femur fracture plus 40% blood volume hemorrhage) groups. One, 4, and 7 days after injury, splenic macrophages were isolated and assayed for expression of Cox-2 and production of PGE2. In addition, the effect of pharmacologically inhibiting Cox-2 or knocking out the Cox-2 gene on trauma-induced suppression of splenocyte mitogenesis was determined.


RESULTS
Trauma led to increased expression of Cox-2, enhanced synthesis of PGE2, and suppressed splenocyte mitogenesis. Both pharmacologic inhibition and genetic deletion of Cox-2 abrogated trauma-mediated suppression of splenocyte mitogenesis.


CONCLUSIONS
These experiments link trauma-induced increases in Cox-2 expression and PGE2 production to reduced immune function. Cox-2 represents a potential pharmacologic target to prevent or reverse trauma-induced immunosuppression.
Mackrell
P J
PJ
Departments of Surgery, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, NY10021, USA.
Daly
J M
JM
Mestre
J R
JR
Stapleton
P P
PP
Howe
L R
LR
Subbaramaiah
K
K
Dannenberg
A J
AJ
D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004790:Enzyme Induction; D005260:Female; D007108:Immune Tolerance; D007527:Isoenzymes / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D014947:Wounds and Injuries / Q000201:enzymology / Q000276:immunology*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone