LPS-Induced Activation of Primed Murine Peritoneal Macrophages Is Modulated by Prostaglandins and Cyclic Nucleotides

Murine peritoneal macrophages primed in vivo by trehalose dimycolate (TDM) express cytostatic activity against tumor cells after treatment in vitro with; 10 mg/ml lipopolysaccharide (LPS) during a 4-hr period (activation step). There is a strict correlation (P <0.0001) between acquisition of antitumoral activity and induction of NO synthase quantified by its end products citrulline and NO-2. LPS also stimulates the release of cyclooxygenase products which exert a retroinhibitory action on NO synthase and cytostatic activities, as judged by an increase of both parameters by indomethacin (1 μM) and a decrease by externally added PGE2 (1 μM). LPS increases cellular and extracellular cAMP levels through an indomethacin-sensitive pathway, pointing to cAMP as a second messenger in the retroinhibitory action of LPS-induced prostaglandins. In fact, the addition of 8-bromo-cAMP or of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine during the activation step decreases NO synthase activity; however, at the same time these drugs increase the apparent efficiency of NO as an antitumor agent.