THE ROLE OF PROSTAGLANDIN-E2 IN IMMUNE SUPPRESSION FOLLOWING INJURY

It has been thought for some time that prostaglandin E2 (PGE2) released from activated monocytes/macrophages may contribute to the suppression of immunity seen after burns and major injury because PGE2 inhibits the activation of T lymphocytes. To clarify this issue, we studied 15 patients with total body surface area burns of 20% to 90% (mean, 48%). Peripheral blood mononuclear cells (PBMC) were obtained from these patients one to two times each week for 1 month after burn and were stimulated with the T-cell mitogen phytohemagglutinin (PHA). On 14 occasions the PBMCs from eight patients were significantly suppressed (30% or more) in their response to PHA (suppressed [sup] burn) as compared with PBMCs from normal controls. In 38 instances PBMCs from 12 patients were not significantly suppressed in PHA (nonsuppressed [nonsup] burn). Sup burn PBMCs and control PBMCs were cultured with or without the addition of the cyclooxygenase (CO) inhibitor indomethacin (Indo, 1-mu-g/mL) and studied for PHA response and the production of the stimulatory cytokine interleukin-2 (IL-2). Indo partially restored the PHA response of sup burn PBMCs to normal. Sup burn PBMCs also were deficient in production of IL-2. Indo increased IL-2 production by sup burn PBMCs significantly more (160% +/- 20%, p < 0.005) than control (57% +/- 5%) and nonsup PBMCs (67% +/- 8%). Next inhibition of the PHA response of PBMCs from 12 burn patients and 17 controls was studied by exogenous PGE2. At all time periods after burn injury, patients' PBMCs were significantly more sensitive to inhibition by PGE2 (50% inhibition at 10 mol/L [molar] PGE2) than PBMCs from normal controls (50% inhibition at 10(-6) mol/L PGE2) with maximum sensitivity occurring 8 to 14 days after injury. Peripheral blood mononuclear cells from patients with more than 40% burns were significantly (p < 0.05) more sensitive to PGE2 than those from patients with lesser burns. Interleukin-2 was added to cultures of sup burn PBMC, nonsup burn PBMC, and controls containing 10(-7) mol/L PGE2. Interleukin-2 totally reversed PGE2 inhibition of the PHA response in PBMC from both controls and burn patients. Because endotoxin leak from the gut has been implicated as a trigger for a number of the metabolic and immunologic abnormalities following injury, the authors looked for the effect of a bolus infusion of Escherichia coli endotoxin (Endo, 4 ng/kg) in seven normal healthy volunteers on the response of PBMC to PHA and on the production of PGE2 and IL-2. The PHA response and IL-2 production were both significantly (p < 0.01) suppressed 4 hours after Endo, returning to normal by 24 hours. At 4 hours PBMCs were also significantly more sensitive (p < 0.001) to exogenous PGE2. Production of PGE2 by adherent PBMCs was maintained at normal levels at 4 hours and increased markedly by 24 hours after Endo. The CO inhibitor ibuprofen (800 mg 2 hours before and at the time of Endo infusion) prevented a significant decrease in PHA response and IL-2 production by PBMCs and blunted the increased PGE2 production 24 hours after Endo. The in vitro addition of Indo partially and exogenous IL-2 completely restored the PHA response to normal. Exogenous IL-1 had no effect when added to cultures of PBMCs from Endo-treated volunteers. It is concluded that (1) PGE2 has a role in the suppression of immunity after burn injury; (2) PGE2 exerts its suppressive effect principally by inhibition of lymphocyte IL-2 production; (3) endotoxin mimics the effect of injury on PGE2 production, T-cell activation, and IL-2 production; (4) administration of CO inhibitors is likely to be essential for the success of clinical regimens designed to correct the immune suppression that follows major injury.