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Inhibition of macrophage mediated cytotoxicity by exogenous adenosine 5'-triphosphate
Abstract:
Peripheral blood monocyte derived macrophages from normal donors can be activated with lipopoly-saccharide (LPS) to kill human tumor cells. However, if adenosine 5'-triphosphate (ATP) is added to the macrophage-tumor cell suspensions in micromolar concentrations (10-100 microM), there is marked inhibition of macrophage mediated cytotoxicity. The inhibitory activity was specific to ATP; as it was not demonstrated with GTP, UTP, CTP, AMP or ADP. In addition, this inhibitory activity resulted from an effect of ATP on the effector cells rather than the target cells. When the effector cells were preincubated with ATP they became incapable of killing the tumor cells whereas preincubation of the target cells with ATP had no effect on their ability to be killed by the macrophages. Cytotoxicity was also inhibited when 100 microM of ATP were added to the macrophage monolayers either at the time of addition of the tumor cells or 15-60 min after addition of the tumor cells whereas no inhibition of cytotoxicity occurred when ATP was added more than 1 hr after the initiation of the cytotoxic reaction.
Insights
Adenosine 5'-triphosphate (ATP) inhibits macrophage-mediated killing of tumor cells. This inhibitory effect is specific to ATP and acts on the effector macrophages, not the tumor cells.
Area of Science:
- Immunology
- Cell Biology
Background:
- Macrophages are immune cells that can be activated to kill tumor cells.
- Lipopolysaccharide (LPS) is a known activator of macrophages.
Purpose of the Study:
- To investigate the effect of adenosine 5 -triphosphate (ATP) on macrophage-mediated cytotoxicity against tumor cells.
Main Methods:
- Peripheral blood monocyte-derived macrophages were activated with LPS.
- Tumor cells were co-cultured with activated macrophages.
- ATP was added at various concentrations and time points to assess its effect on cytotoxicity.
Main Results:
- Micromolar concentrations of ATP (10-100 microM) significantly inhibited macrophage-mediated cytotoxicity.
- The inhibitory effect was specific to ATP and not observed with other nucleotides (GTP, UTP, CTP, AMP, ADP).
- ATP exerted its inhibitory effect on the effector macrophages, not the target tumor cells, and required addition within 60 minutes of co-culture initiation.
Conclusions:
- ATP acts as a potent inhibitor of LPS-activated macrophage cytotoxicity.
- The findings suggest a regulatory role for extracellular ATP in macrophage-mediated anti-tumor immune responses.
