Prostaglandin E2 affects differently the release of inflammatory mediatorsfrom resident macrophages by LPS and muramyl tripeptides

LPS and MTP-PE (liposome-encapsulated N-acetylmuramyl-L-alanyl-D-isoglutami nyl-L-alanine-2-:[1',2'-dipalmitoyl-2ni-glycero-3-(hydroxy-phosphoryl-oxyl) ] etylamide) induce in liver macrophages a synthesis and release of TNF-alp ha, nitric oxide and prostanoids. Both agents induce an expression of mRNA' s encoding TNF-alpha, inducible nitric oxide synthase (iNOS) and cyclooxyge nase (COX)-2, and of corresponding proteins. LPS and MTP-PE induce a rapid activation of the extracellular regulated kinase (ERK) isoenzymes-2 and -2. Inhibition of map kinase isoenzymes leads to a decreased release of TNF-al pha, nitric oxide and prostaglandin (PG) E-2 after both agents. The transcr iption factors NF-kappa B and AP-1 are strongly activated by LPS within 30 minutes. MTP-PE induces a weak activation of both transcription factors onl y after 5 hours, Inhibition of NF-kappa B inhibits the LPS- but not the MTP -PE-induced release of TNF-alpha, nitric oxide and PGE(2). PGE(2) release a fter LPS is higher than after MTP-PE. Exogenously added PGE(2) inhibits the activation of map kinase and TNF-alpha release by LPS, but not by MTP-PE. Release of nitric oxide after LPS and MTP-PE is enhanced after prior additi on of PGE(2). PGD(2) is without any effect. MTP-PE, but not LPS, induces a cytotoxicity of Kupffer cells against P815 tumor target cells. The MTP-PE-i nduced cytotoxicity is reduced by TNF-alpha neutralizing antibodies, indica ting the involvement of TNF-alpha. Thus our results suggest that the differ ent potencies of LPS and MTP-PE as immunomodulators probably result from di fferent actions on Kupffer cells, resulting in differences in the amounts a nd kinetics of released TNF-alpha and PGE(2), and that PGE(2) plays an impo rtant regulatory role in the action of LPS, but not in the actions of MTP-P E.