Interaction of gelonin with macrophages: effect of lysosomotropic amines

The cytotoxic effects of gelonin on various phagocytic and nonphagocytic cells were studied. Peritoneal exudate cells (PEC) are found to be more sensitive to gelonin compared to P388D1 and J774A.1 cells, nonphagocytic cells being the least sensitive. While chloroquine markedly enhances the cytotoxicity of gelonin in macrophages (greater than 100-fold) ammonium chloride confers protection. A higher rate of uptake of 125I-gelonin in PEC (7 times the rate observed in other cells) is probably mediated by an interaction of terminal mannose residues of gelonin with mannose receptors on PEC plasma membrane as inferred from a pronounced inhibitory effect of mannan. In contrast to a pronounced inhibitory effect of mannan on the uptake of gelonin in PEC (7-fold), the cytotoxicity is reduced only by 2-fold. On the other hand, mannan has little or no effect on enhancement of the toxicity of gelonin by chloroquine. The studies have suggested that the internalization of gelonin in PEC may involve two pathways: (a) mannose receptor-mediated endocytosis, which plays a minor role in the intoxication process, and (b) nonspecific fluid phase pinocytosis, which is susceptible to enhancement by chloroquine and has a major role to play in the manifestation of the toxic effect of gelonin. In macrophage-like cells only the latter pathway operates.