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[Experimental analysis of cytotoxicity mediated by activated macrophages against glioma cells in mice]
1Department of Neurosurgery, Faculty of Medicine, Kyoto University.
Abstract:
Macrophage (M phi) has a very important role in host natural defence and tumor cell killing. Activated M phi with tumor cytotoxicity can be induced by various lymphokines, such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-4, granulocyte macrophage-colony stimulating factor (GM-CSF), and macrophage-colony stimulating factor (M-CSF), but also by various bacterial products, such as lipopolysaccharide (LPS), Bacillus Calmette Guérin (BCG), corynebacterium parvum (C.p.), and muramyl-dipeptide (MDP). Although the brain is considered as an "immunologically privileged site", it has been demonstrated that in malignant brain tumors infiltration of lymphocytes or M phi can be seen in tissue samples. This may suggest that immune surveillance exists in the brain. But the biological significance of infiltrative M phi is unclear. The purpose of this study is to confirm the significant generation of activated M phi with cytotoxicity to glial tumor cells and to elucidate the cytotoxic mechanism associated with cellular interaction between effector M phi and target cells. This is the first report on experimental analysis of cytotoxicity mediated by activated M phi against glioma cells in mice. The cytotoxicity mediated by murine peritoneal activated M phi was examined against 3 kinds of murine glioma cell lines; VM-Glioma (spontaneously occurring astrocytoma of the VM mouse origin, H-2b), RSV-M (Schmitt-Ruppin Rous sarcoma virus-induced malignant glioma of the C3H/He mouse origin, H-2k), and 203-Glioma (methylcholanthrene-induced ependymoblastoma of the C57BL/6 mouse origin, H-2b). Activated M phi were obtained from peritoneal exudate cells of 4 strains of mice, C57BL/6 (H-2b), C3H/He (H-2k), DBA/2 (H-2d), and BALB/c (H-2d), following intraperitoneal injection of (1) LPS 200 micrograms, (2) BCG 200 micrograms, (3) C.p. 200 micrograms, (4) MDP 350 micrograms, and (5) IFN-gamma 10(3) units, 7 days prior to 20 hr 51Cr release-cytotoxicity assay. Of the various combination of mouse strains and activating agents tested, that of activated M phi of the C3H/He mouse with induction by LPS had the most tumoricidal effect against the glioma cells, which was not MHC restricted. Although LPS-activated M phi underwent marked loss of cytotoxicity within 24 hr following initiation of in vitro culture, this 20 hr pretreatment with IFN-gamma or TNF-alpha inhibited this reduction in tumoricidal effects in a dose dependent fashion.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Activated macrophages exhibit significant cytotoxicity against glioma cells, with lipopolysaccharide (LPS) induction in C3H/He mice showing the most potent tumoricidal effect. Interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) can enhance this macrophage-mediated anti-glioma activity.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Context:
- Macrophages (M phi) play a crucial role in host defense and tumor cell killing.
- Despite the brain's immune privilege, macrophages infiltrate malignant brain tumors, suggesting a role in immune surveillance.
- The precise function and cytotoxic mechanisms of these infiltrating macrophages in the brain remain unclear.
Purpose:
- To confirm the generation of activated macrophages with cytotoxicity against glial tumor cells.
- To elucidate the cytotoxic mechanisms involving cellular interactions between effector macrophages and target glioma cells.
- To provide the first experimental analysis of macrophage-mediated cytotoxicity against glioma cells in mice.
Summary:
- Murine peritoneal macrophages were activated using various agents including lipopolysaccharide (LPS), Bacillus Calmette Guérin (BCG), corynebacterium parvum (C.p.), muramyl-dipeptide (MDP), and interferon-gamma (IFN-gamma).
- Cytotoxicity was assessed against three murine glioma cell lines (VM-Glioma, RSV-M, 203-Glioma).
- Activated macrophages from C3H/He mice induced by LPS demonstrated the most significant tumoricidal effect against glioma cells, independent of MHC restriction.
- Pretreatment with IFN-gamma or tumor necrosis factor-alpha (TNF-alpha) inhibited the loss of cytotoxicity in LPS-activated macrophages during in vitro culture.
Impact:
- This study demonstrates the potential of activated macrophages as a therapeutic strategy against gliomas.
- It provides insights into the mechanisms of macrophage-mediated anti-tumor immunity within the central nervous system.
- Findings suggest that macrophage activation and modulation could be a viable approach for brain tumor treatment.