Delineation of the mechanism of inhibition of human T cell activation by PGE2.

R Minakuchi, MC Wacholtz, LS Davis… - Journal of immunology …, 1990 - journals.aai.org
R Minakuchi, MC Wacholtz, LS Davis, PE Lipsky
Journal of immunology (Baltimore, Md.: 1950), 1990journals.aai.org
The capacity of PGE2 to inhibit human T cell responses was examined by investigating its
effect on mitogen-induced IL-2 production and proliferation of highly purified CD4+ T cells.
PGE2 inhibited both PHA and anti-CD3 induced proliferation and IL-2 production by an
action directly on the responding T cell. Inhibition of IL-2 production reflected decreased
accumulation of mRNA for IL-2. A variety of other cAMP elevating agents exerted similar
inhibitory effects. Inhibition of proliferation could be overcome by supplemental IL-2, PMA, or …
Abstract
The capacity of PGE2 to inhibit human T cell responses was examined by investigating its effect on mitogen-induced IL-2 production and proliferation of highly purified CD4+ T cells. PGE2 inhibited both PHA and anti-CD3 induced proliferation and IL-2 production by an action directly on the responding T cell. Inhibition of IL-2 production reflected decreased accumulation of mRNA for IL-2. A variety of other cAMP elevating agents exerted similar inhibitory effects. Inhibition of proliferation could be overcome by supplemental IL-2, PMA, or the anti-CD28 mAb 9.3. Although PMA and 9.3 markedly increased the amount of IL-2 produced by mitogen-stimulated T cells, the percentage inhibition of IL-2 secretion caused by PGE2 and other cAMP elevating agents remained comparable in these costimulated cultures. Rescue of T cell DNA synthesis by these agents appeared to reflect the finding that, although PGE2 markedly inhibited IL-2 production, the absolute amount of IL-2 produced was increased sufficiently to sustain mitogen-induced proliferation. As anticipated, PGE2, forskolin, and cholera toxin increased T cell cAMP levels. The quantity of cellular cAMP generated in response to PGE2, cholera toxin, and forskolin could be inhibited by PMA or 2',5'-dideoxyadenosine. Using these reagents, the inhibitory effects of PGE2 were found to reflect intracellular cAMP levels, but only within a very narrow range. The results indicate that by elevating cAMP levels, PGE2 inhibits human T cell IL-2 production at a point that is common to both the CD3 and CD28 signaling pathways.
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