Characterization of the 3′,5′-cyclic adenosine monophosphate-mediated regulation of IL2 production by T cells and Jurkat cells

Abstract

The effect of cyclic AMP-elevating agents on mitogen-stimulated IL2 production was examined. Prostaglandin E 2 (PGE 2) inhibited IL2 production by human peripheral blood T cells stimulated with PHA. In contrast, PGE 2 did not inhibit PHA-stimulated IL2 production by the human leukemic T cell line, Jurkat, and often slightly enhanced IL2 production by those cells. Other cyclic adenosine monophosphate (cAMP) elevating agents (forskolin, isoproterenol, and the cAMP analogue, dibutyryl cAMP) also inhibited lectin-stimulated IL2 production by T cells, but could not inhibit IL2 production by Jurkat cells. Of the cAMP-elevating agents examined, only cholera toxin (CT) inhibited IL2 production by both Jurkat cells and peripheral blood T cells. Although phorbol myristate acetate (PMA) greatly enhanced PHA-stimulated IL2 production by Jurkat cells, CT remained markedly inhibitory. The combination of PMA and the calcium ionophore, ionomycin, also induced IL2 production by Jurkat cells, and this was similarly suppressed by CT, suggesting that a step after initial second messenger generation was inhibited. A prolonged increase in intracellular cAMP levels was induced by CT in both T cells and Jurkat cells, but the maximal level and the length of elevation achieved in T cells were much less than those observed in Jurkat cells. In contrast, PGE 2 caused only a modest and transient increase in intracellular cAMP levels in Jurkat cells compared to that noted with T cells. PGE 2 induced a more marked and sustained increase in cAMP levels in Jurkat cells treated with isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor. Moreover, in the presence of IBMX, PGE 2 caused a marked inhibition of IL2 production by PHA-stimulated Jurkat cells. Differences in the capacity of PGE 2 to induce cAMP could not be explained by disparities in the level of cAMP phosphodiesterase activity as this was comparable in Jurkat cells and in T cells. Thus, these observations indicate that IL2 production by both peripheral T cells and Jurkat cells can be modulated by cAMP-elevating agents. The data suggest that the diminished capacity of PGE 2 to inhibit IL2 production by Jurkat cells reflects both a diminished capacity of PGE 2 to induce increases in cAMP levels in these cells and an increase in the threshold of cAMP required to inhibit Jurkat cells.