Prostaglandin E2 Affects Differently the Release of Inflammatory Mediators from Resident Macrophages by LPS and Muramyl Tripeptides

Abstract

LPS and MTP‐PE (liposome‐encapsulated N‐acetylmuramyl‐L‐alanyl‐D‐isoglutaminyl‐L‐alanine‐2‐:[1′,2′‐dipalmitoyl‐sni‐glycero‐3‐(hydroxy‐phosphoryl‐oxyl)] etylamide) induce in liver macrophages a synthesis and release of TNF‐α, nitric oxide and prostanoids. Both agents induce an expression of mRNA′s encoding TNF‐α, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)‐2, and of corresponding proteins. LPS and MTP‐PE induce a rapid activation of the extracellular regulated kinase (ERK) isoenzymes‐1 and ‐2. Inhibition of map kinase isoenzymes leads to a decreased release of TNF‐α, nitric oxide and prostaglandin (PG) E₂ after both agents. The transcription factors NF‐κB and AP‐1 are strongly activated by LPS within 30 minutes. MTP‐PE induces a weak activation of both transcription factors only after 5 hours. Inhibition of NF‐κB inhibits the LPS‐ but not the MTP‐PE‐induced release of TNF‐α, nitric oxide and PGE₂. PGE₂ release after LPS is higher than after MTP‐PE. Exogenously added PGE₂ inhibits the activation of map kinase and TNF‐α release by LPS, but not by MTP‐PE. Release of nitric oxide after LPS and MTP‐PE is enhanced after prior addition of PGE₂. PGD₂ is without any effect. MTP‐PE, but not LPS, induces a cytotoxicity of Kupffer cells against P815 tumor target cells. The MTP‐PE‐induced cytotoxicity is reduced by TNF‐α neutralizing antibodies, indicating the involvement of TNF‐α. Thus our results suggest that the different potencies of LPS and MTP‐PE as immunomodulators probably result from different actions on Kupffer cells, resulting in differences in the amounts and kinetics of released TNF‐α and PGE₂, and that PGE₂ plays an important regulatory role in the action of LPS, but not in the actions of MTP‐PE.