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 microgram/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 less than 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(-8) 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 less than 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Grbic
J T
JT
Department of Surgery, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115.
Mannick
J A
JA
Gough
D B
DB
Rodrick
M L
ML
D000293:Adolescent; D000328:Adult; D000368:Aged; D002056:Burns / Q000276:immunology*; D015232:Dinoprostone / Q000276:immunology*; D004731:Endotoxins / Q000276:immunology; D004926:Escherichia coli; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007213:Indomethacin / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D008875:Middle Aged
D004731:Endotoxins; D007376:Interleukin-2; D015232:Dinoprostone; D007052:Ibuprofen; D007213:Indomethacin