Defective IFN-gamma production in the human neonate. II. Role of increased sensitivity to the suppressive effects of prostaglandin E.
Analysis of endogenous production and effects of exogenous addition of interleukin 2 (IL 2), leukotrienes (LT), and prostaglandin E (PGE) has been used to investigate the dysregulation responsible for impaired PHA-induced IFN-gamma secretion by cord blood leukocytes (CBL). The addition of LT or IL 2 could not reverse the IFN defect of CBL. The production of these two mediators was found to be normal in CBL cultures. CBL and control leukocytes from adult donors produced comparable amounts of PGE2. In contrast, sensitivity to the suppressive effects of PGE2 on IFN-gamma secretion was much higher with CBL than with control leukocytes. Treatment with indomethacin reversed the IFN-gamma defect with most CBL tested, and the addition of physiologic amounts of PGE2 to indomethacin-treated cultures resulted in a profound impairment of IFN-gamma production similar to that of untreated CBL cultures. Preincubation of CBL for 24 hr before PHA stimulation resulted in restoration of a normal sensitivity to exogenous PGE2, in parallel with correction of the IFN-gamma defect. Our observations suggest that the impairment of IFN-gamma secretion in neonates is not due to deficient amplification circuits, but is the consequence of an exaggerated cellular sensitivity to the suppressive effects of PGE produced endogenously in normal amounts.
Wakasugi
N
N
Virelizier
J L
JL
Arenzana-Seisdedos
F
F
Rothhut
B
B
Huerta
J M
JM
Russo-Marie
F
F
Fiers
W
W
D000328:Adult; D000367:Age Factors; D015232:Dinoprostone; D005260:Female; D005312:Fetal Blood / Q000276:immunology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000276:immunology; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology*; D007975:Leukotriene B4 / Q000494:pharmacology; D011247:Pregnancy; D011458:Prostaglandins E / Q000032:analysis / Q000494:pharmacology*; D013189:SRS-A / Q000276:immunology
D007376:Interleukin-2; D011458:Prostaglandins E; D013189:SRS-A; D007975:Leukotriene B4; D007371:Interferon-gamma; D015232:Dinoprostone; D007213:Indomethacin