Dimethylnitrosamine (DMN), a potent immunomodulatory agent, produces its effects on cell-mediated immune reactions through alterations in macrophage production and/or macrophage maturation/differentiation from bone marrow stem cells. Macrophages obtained by the in vitro culture of bone marrow from animals exposed to DMN in vivo (bone marrow-derived macrophages, BMDM) demonstrated enhanced cytotoxicity against L929 target cells. The enhanced cytotoxicity was also present in concanavalin A- and Corynebacterium parvum-elicited peritoneal exudate cells (PEC) obtained from DMN-exposed animals while thioglycollate-elicited PEC from DMN-exposed animals displayed no increase in their cytotoxic activity as compared to vehicle-exposed animals. However, treatment of thioglycollate-elicited PEC with interferon-γ induced cytotoxic activity in PEC obtained from DMN-exposed animals but not in PEC obtained from control animals. BMDM obtained from DMN-exposed mice also demonstrated an alteration in the kinetics of the expression of the membrane-associated transferrin-binding receptor (mTFR), a marker of the activational status of macrophages. BMDM from animals exposed to DMN in vivo exhibited maximal expression of mTFR on day 7 of culture in vitro as compared to day 5 for BMDM from vehicle-exposed animals. C. parvum- and concanavalin A-elicited PEC from DMN-exposed animals showed dose-related decreases in their expression of mTFR which were associated with their expected enhanced cytotoxicity. Likewise, thioglycollate-elicited PEC from DMN-exposed mice had dose-related decreases in mTFR expression and total transferrin-binding activity, suggesting a change in their state of activation. No alterations in mTFR expression were observed in splenic macrophages. BMDM cultured with T cell-derived lymphokines known to affect mTFR expression demonstrated enhanced expression of mTFR independent of changes in the cell cycle profiles. Furthermore, while lymphokines enhanced mTFR expression, there was no alteration in the kinetics of mTFR expression by BMDM obtained from DMN- or vehicle-exposed animals. These results support the hypothesis that DMN-induced alterations in macrophage hematopoietic differentiation/maturation are manifested in changes in macrophage function.
- Macrophage anti-tumor activity
- Transferrin receptor
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