Prostaglandin E2 suppresses phytohemagglutinin-induced immune responses of normal human mononuclear cells by decreasing intracellular glutathione generation, but not due to increased DNA strand breaks or apoptosis.
Prostaglandin E2 (PGE2) at concentrations more than 1 x 10(-8) M markedly suppressed the cell proliferation and release of soluble molecules of interleukin-2 receptor (sIL-2R), CD4 (sCD4) and CD8 (sCD8) from phytohemagglutinin (PHA)-stimulated normal human mononuclear cells (MNC) in a dose-related manner. To further elucidate the subcellular mechanism of the inhibitory effect of PGE2 on PHA-stimulated MNC, intracellular concentration of glutathione (GSH) in PHA-stimulated MNC was sequentially measured from day 1 to day 3 by enzymic method. Furthermore, the effect of PGE2 on nuclear DNA including DNA strand breaks in alkali treatment and DNA fragmentation (apoptosis) of PHA-stimulated MNC were also measured. We found intracellular GSH levels were significantly decreased in the early stage of lymphocyte activation (day 1), but no evidence of increased DNA strand breaks or apoptotic process appeared in 3-day culture. In addition, butathione sulfoximine (a specific GSH inhibitor) and dibutyryl cyclic AMP also exhibited both proliferation inhibition and GSH-decreasing effects on PHA-stimulated MNC as well as PGE2. These results suggest that the immunosuppressive effect of PGE2 is mediated by the decreased generation of intracellular GSH, but not by the increased DNA strand breaks or apoptotic mechanism in the cells.
Yu
C L
CL
Department of Medicine, Veterans General Hospital-Taipei, Taiwan, Republic of China.
Liu
C L
CL
Tsai
C Y
CY
Sun
K H
KH
Liao
T S
TS
Lin
W M
WM
Chen
H L
HL
Yu
H S
HS
D000963:Antimetabolites / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003994:Bucladesine / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D016516:CD4-CD8 Ratio / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage; D015232:Dinoprostone / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005978:Glutathione / Q000096:biosynthesis*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010835:Phytohemagglutinins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013936:Thymidine / Q000378:metabolism
D000963:Antimetabolites; D010835:Phytohemagglutinins; D015375:Receptors, Interleukin-2; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D003994:Bucladesine; D005978:Glutathione; D015232:Dinoprostone; D013936:Thymidine