Eicosanoid Regulation of Macrophage-Mediated Anti-Tumor Function

Abstract

When phospholipids deliver free arachidonic acid (AA), it can be in macrophages metabolized either into the cyclooxygenase pathway or into lipoxygenase products. The release of eicosanoids is intimately related to the activation state of macrophages. The production of the cyclooxygenase metabolite PGE₂ is inversely correlated with the activation state. Furthermore PGE₂, via receptor-mediated activation of adenylate cyclase, is involved in elevated levels of intracellular cyclic AMP in macrophages. Increased levels of cyclic AMP are associated with inhibition of macrophage functions and PGE₂ which activates the adenylate cyclase, is recognized as deactivator of macrophages. In this context, inhibitors of cyclooxygenase promote the activation of macrophages, as i.a. shown by enhanced release of lysosomal enzymes (Schenkelaars & Bonta 1986). In contrast to the above, the lipoxygenase pathway favours the activation of macrophages. Several immunological events are associated with increased biosynthesis of leukotrienes (LTs) (Rola-Pleszczynski & LeMaire 1986). Macrophages were shown to be responsive to exposure of either LTC₄ or LTD₄, both of them inducing the release of several products of the cyclooxygenase pathway. Using the secretion of a lysosomal enzyme as a marker of cell activity, LTC₄ was also shown to trigger the activation of macrophages. Thus LTC₄ proved to enhance the enzyme secretion of macrophages, whereas PGE₂ inhibited this event. Because lysosomal enzyme release was observed with a lower concentration of LTC₄ than necessary to induce the biosynthesis of PGE₂ it was proposed that the enzyme secretion is the primary event and that the subsequent release of PGE₂ serves to limit the activating function of the peptidoleukotriene. In that case full expression of LT induced activation would only be observed in the absence of endogenous, PGE₂. Indeed, it was shown that inhibitors of cyclooxygenase promote the LTC₄-induced release of a lysosomal enzyme (Schenkelaars & Bonta 1986). The finding that LTs promote the production of PGE₂, — the cyclooxygenase metabolite which suppresses macrophages — indicates that the action of LTs is self-limiting and that eicosanoid formation is, at least partially, regulated by interactions between the different metabolites of AA. The more recent observation, showing that the calcium flux-induced release of LTB₄ is counteracted by PGE₂ and augmented by inhibitors of cyclooxygenase (Elliott et al. 1988b), gives further support to the concept that the dynamic state of activation of macrophages is maintained by balanced interactions between endogenous PGE₂ and leukotrienes. Macrophage cytotoxicity or cytostasis towards tumor cells is a characteristic expression of macrophage activation. Studies, which were aimed to investigate the role of eicosanoids in the anti-tumor function of macrophages, represented a logical move.