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Prostaglandins are known to influence a variety of functional activities of T cells. Prostaglandins such as PGE2 suppress T-cell function by mechanisms that depend on their capacity to stimulate adenylate cyclase and to increase cyclic AMP (cAMP) levels. PGE2 inhibits both antigen- and mitogen-stimulated T-cell DNA synthesis and IL-2 production. Inhibition of IL-2 production is a primary inhibitory effect of PGE2, as supplementation with IL-2 can overcome much of the PGE2-mediated inhibition of T-cell DNA synthesis. Study of purified human T cells has revealed a number of mechanisms by which PGE2 and increases in cAMP levels inhibit IL-2 production. PGE2/cAMP inhibit activation of phospholipase C, one of the early biochemical steps involved in T-cell activation resulting from ligation of the T-cell receptor-CD3 complex. This can result in diminished mobilization of intracellular Ca2+ stores or activation of protein kinase C. This is not the sole mechanism by which PGE2 inhibits IL-2 production, however, as phorbol esters, which directly activate protein kinase C, cannot prevent inhibition of IL-2 production. Even if initial activation is successful, elevation of cAMP levels can independently modulate gene transcription, leading to decreased mRNA levels for IL-2. In addition to suppressing T-cell responses, elevation of cAMP levels, which may also occur normally during T-cell activation, may be required for certain functional activities of T cells, including capping of the CD3-T-cell receptor complex or expression of the differentiation marker CD7. In this regard, PGE2 or other cAMP-elevating agents can facilitate cell cycle progression after initial receptor-initiated biochemical events are accomplished. Thus, PGE2 and other cAMP-elevating agents exert potent and specific regulatory influences on specific aspects of T-cell responsiveness to antigens and mitogens. |
