LPS and liposome-encapsulated MTP-PE induce liver macrophages cytotoxicity against tumor target cells and a release of TNF-alpha, nitric oxide, and eicosanoids but not a generation of superoxide anions. Neither agent elicits a formation of inositol phosphates, a change in intracellular free calcium, or a translation of protein kinase C-beta. Inhibition or down-regulation of protein kinase C does not inhibit the release of TNF-alpha and nitric oxide but inhibits the formation of prostanoids. In contrast to LPS, liposome -encapsulated MTP-PE induces an elevation of diacylglycerol mass and an enhanced expression of protein kinase C-delta. LPS, but not liposome-encapsulated MTP-PE, elicits an enhanced expression of cytosolic phospholipase A2 and a predominant formation of PGE2. Both agents elicit different responses when given to cells pretreated with one of the immunomodulators, with dexamethasone, or with PGE2. In contrast, to liposome-encapsulated MTP-PE, LPS induces only cytotoxicity when added to liver macrophages simultaneously or a maximum of 2 h before the addition of tumor target cells. The observed differences might reflect partly differences in the potencies of LPS and some liposome-encapsulated MTP-PE as immunomodulators.