Effect of PGE 2 and of agents that raise cAMP levels on macrophage activation induced by IFN‐γ and TNF‐α

The effect of prostaglandin (PG) E 2 on macrophage activation by interferon‐γ (IFN‐γ) and tumor necrosis factor‐α (TNF‐α) was evaluated. Murine macrophages infected with Leishmania enriettii or Leishr mania major were activated by exposure to IFN‐γ (10–50 U/ml) and TNF‐α (30–3000 U/ml), leading to intracellular parasite destruction within 24–48 h. Leishmanicidal activity was markedly increased when activation was performed in the presence of PGE 2 (10 ‐9 ‐10 ‐7 M) or arachidonate (10 ‐5 M, a PG precursor), concomitant with enhanced nitrite release and glucose oxidation through the hexose monophosphate shunt pathway. Conversely, activation was reduced by indomethacin and hydrocortisone, two inhibitors of PG synthesis. Parasite killing and nitrite production were fully restored by exogenous PGE 2 , indicating that inhibition by these drugs was related to their ability to block PG production. PG can stimulate adenylate cyclase, thus raising intracellular cAMP levels. Accordingly, dibutyryl‐cAMP, theophylline (which prevents cAMP breakdown), and forskolin (an activator of adenylate cyclase) all stimulated macrophage activation. Finally, PGE 2 and cAMP enhanced expression of inducible nitric oxide synthase mRNA in response to IFN‐γ and TNF‐α, and this effect was inhibited by the cAMP antagonist 2′‐ O ‐methyl adenosine. These findings are consistent with the hypothesis that PGE 2 acts as a positive agonist in macrophage activation by IFN‐γ and TNF‐α via its capacity to modulate intracellular cAMP levels. .J Leukoc. Biol 58: 217–224; 1995.