Activation of resident tissue-specific macrophages by swainsonine.
The induction of macrophage tumoricidal activity by swainsonine (8a beta-indolizidine-1 alpha, 2 alpha, 8 beta-triol), an indolizidine alkaloid, has been implicated as possibly an important immune effector mechanism involved in the suppression of tumor growth and metastasis in vital organs such as the lung, liver and spleen (Olden, K. et al. The potential importance of swainsonine in therapy for cancers and immunology. Pharmacol. Ther. 50:285-290; 1991). The present study further explores this possibility by determining whether resident tissue-specific macrophages of several mouse strains can be rendered tumoricidal by systemic administration of swainsonine. We found that systemically administered swainsonine could increase the tumoricidal activity of both alveolar (lung) and splenic macrophages. The activity was enhanced as much as 3- to 4-fold over that obtained with macrophages from organs of control animals and was both dose- and time-dependent. The level and extent of activation by swainsonine was comparable to that achieved with traditional macrophage-activating agents, such as lipopolysaccharide and interferon-gamma. The fact that swainsonine activated highly purified (> 95%) cultures of macrophages from the various sources suggests a direct mechanism of activation. Furthermore, the in vivo activation of macrophages in immune-compromised animals (SCID and nude) lends credence to this suggestion. These findings provide a plausible explanation for the observations that systemically administered swainsonine inhibits organ colonization of metastatic cells and growth of SC tumor xenografts, whereas the growth of tumor cells is not inhibited by swainsonine in culture.
Das
P C
PC
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Roberts
J D
JD
White
S L
SL
Olden
K
K
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000188:drug therapy; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D017026:Swainsonine / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D000276:Adjuvants, Immunologic; D008070:Lipopolysaccharides; D007371:Interferon-gamma; D017026:Swainsonine