Accessory cell-derived IL-12 and prostaglandin E2 determine the IFN-gamma level of activated human CD4+ T cells.
IL-12 and PGE2 are two immunomodulators produced by accessory cells (AC) in response to various stimuli. IL- 12 enhances IFN-gamma production by activated CD4+ T cells, whereas PGE2 inhibits the secretion of this cytokine. Because these AC-derived factors exert clearly opposite modulatory effects on IFN-gamma production, we examined 1) the net-IFN-gamma production of CD4+ T cells, stimulated in the presence of both IL-12 and PGE2, 2) the susceptibility of activated CD4+ T cells in time by adding these modulators at different timepoints after stimulation, and 3) the relative contributions of AC-derived IL-12 and PGE2 to IFN-gamma levels by stimulating CD4+ T cells in the presence of LPS-activated monocytes and inhibitors of PGE2 or IL-12. Here, we demonstrate that 1) IL-12 and PGE2 do not abrogate the modulatory action of each other and that the net-IFN-gamma production is determined by their concentration ratio, 2) T cells become insensitive to PGE2, whereas susceptibility to IL-12 is retained after activation, and 3) activated monocytes potently modulate IFN-gamma levels of stimulated CD4+ T cells via release of IL-12 and PGE2. The relative contributions of these AC-derived factors shift in time, due to different production kinetics, from a dominant IL-12 effect to a mixed IL-12/PGE2 effect. Because the net IFN-gamma production of CD4+ T cells is largely determined by the ratio of IL-12 and PGE2 at the timepoint of T cell activation, an imbalance in the production of these immunomodulators may, therefore, lead to immunologic dysfunction.
Hilkens
C M
CM
Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands.
Snijders
A
A
Vermeulen
H
H
van der Meide
P H
PH
Wierenga
E A
EA
Kapsenberg
M L
ML
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002999:Clone Cells; D015232:Dinoprostone / Q000096:biosynthesis* / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis / Q000037:antagonists & inhibitors / Q000187:drug effects*; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D009000:Monocytes / Q000378:metabolism
D000276:Adjuvants, Immunologic; D018664:Interleukin-12; D007371:Interferon-gamma; D015232:Dinoprostone