Evaluation of Misoprostol and Analogs as Inhibitors of T-Cell Activation.
Prostaglandin E(2) (PGE(2)) is known to inhibit in vitro T-cell responses to mitogenic and antigenic stimuli. Interaction of PGE(2) with a G protein-coupled receptor activates adenylyl cyclase, leading to cAMP formation and inhibition of interleukin-2 (IL-2) production and T-cell proliferation. Despite these effects, the application of PGE(2) as an anti-inflammatory agent has been compromised by its unfavorable pharmacodynamic and side-effect profile. Because of the potential utility of synthetic analogs as prostaglandin-based therapeutics, we evaluated the effect of misoprostol and over 100 structural analogs on cAMP formation and T-cell activation. Our results indicate that micromolar concentrations of misoprostol and particular analogs elicited a rapid and substantial rise in cAMP levels in human peripheral blood mononuclear cells. Analogs which increased cAMP also suppressed IL-2 production and T-cell growth in vitro, whereas those devoid of suppressive activity weakly induced nucleotide synthesis. Despite extensive chemical alteration of the prostanoid structure, no single analog was superior to misoprostol in inducing cAMP or modulating T-cell activity. Misoprostol and suppressive analogs were also evaluated in vivo in a murine model of antigen-induced T-cell proliferation. Prostaglandins, administered at maximum tolerable doses, were ineffective in blocking a T-cell response to alloantigenic stimulation, whereas cyclosporine and prednisolone were potent inhibitors of this response. Overall, our results indicate that misoprostol and related analogs suppress T-cell activation in vitro but require concentrations 1000-fold greater than the low nanomolar plasma levels achieved with clinical doses of misoprostol. Whether misoprostol analogs of sufficient potency can be developed for pharmacologic attentuation of T-cell activation in vivo remains to be determined.
Mnich
Stephen J.
SJ
Department of Chemistry, G.D. Searle & Co., St. Louis, USA.
Collins
Paul W.
PW
Gasiecki
Alan F.
AF
Kramer
Steven W.
SW
Gregory
Susan A.
SA
Portanova
Joseph P.
JP