Induction of macrophage tumoricidal activity, major histocompatibility complex class II antigen (Iak) expression, and interleukin-1 production by swainsonine

Previous studies in our laboratory have shown that the reported antitumor activity of systemically administered swainsonine, an indolizidine alkaloid, is due at least in part to immune modulation involving effector cells (Humphries, M.J.; Matsumoto, K; White, S.L.; Olden, K. Cancer Res. 48:1410-1415; 1988 and White, S. L.; Schweitzer, K.; Humphries, M.J.; Olden, K. Biochem. Biophys. Res. Commun. 150:615-625; 1988). In this report, studies are presented to show that swainsonine was effective in activating peritoneal macrophages to cytotoxicity against tumor cells. Stimulation of tumoricidal activity of macrophages was associated with increased secretion of interleukin-1 (IL-1) and expression of the Iak major histocompatibility complex (MHC) antigen on the cell surface. The 3-fold stimulation of cytotoxicity observed in these in vivo studies was comparable to that obtained with Corynebacterium parvum, a commonly used in vivo activating agent. The in vitro incubation of thioglycollate-elicited peritoneal macrophages with swainsonine consistently resulted in levels of activation (6- to 8-fold) comparable to that obtained by treatment with known in vitro macrophage activating agents such as lipopolysaccharide (LPS) or recombinant gamma-interferon (rIFN-gamma). The stimulation observed by using swainsonine in combination with LPS was additive, suggesting different mechanisms of action. These studies have important implications not only for treatment of cancer, infectious diseases, and immune suppressive disorders, but also for elucidation of the mechanism of macrophage activation.