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Inhibition of human granulocyte function by methotrexate
Abstract:
Patients receiving cytotoxic drugs are at an increased risk of bacterial infection. Drug-induced leukopenia may be responsible for depression of host defenses; however, there is little information concerning the qualitative effects, if any, of cytotoxic agents on granulocyte antibacterial activity. Since methotrexate is now being used in massive doses in vivo, we investigated the effects of this drug on antibacterial and metabolic functions of normal polymorphonuclear leukocytes in vitro. Phagocytosis, quantitative protein iodination, and staphylococcal killing of normal polymorphonuclear leukocytes were found to decrease with exposure to increasing concentrations of methotrexate. The effects of methotrexate on these cell functions were rapid in onset and readily reversed by washing the cells, suggesting a locus of action on the cell membrane rather than at the level of nucleic acid synthesis. Exposure of cells to similar concentrations of folic acid or folinic acid produced no impairment of bacterial phagocytosis, suggesting that the observed effects are specific for methotrexate. The concentrations of methotrexate that produced these impairments are readily achieved in vivo and may alter antibacterial defenses in patients receiving this therapy.
Insights
Methotrexate impairs polymorphonuclear leukocyte functions, reducing bacterial phagocytosis and killing. These rapid, reversible effects suggest methotrexate impacts cell membranes, potentially weakening host defenses in patients.
Area of Science:
- Immunology
- Pharmacology
- Cell Biology
Background:
- Cytotoxic drugs increase bacterial infection risk in patients.
- Drug-induced leukopenia may suppress host defenses.
- Limited data exists on cytotoxic agents' effects on granulocyte antibacterial activity.
Purpose of the Study:
- Investigate methotrexate's impact on polymorphonuclear leukocyte (PMN) antibacterial and metabolic functions in vitro.
- Determine if methotrexate affects phagocytosis, protein iodination, and bacterial killing.
- Assess the reversibility and specificity of methotrexate's effects on PMNs.
Main Methods:
- Exposed normal human PMNs to varying concentrations of methotrexate in vitro.
- Assessed phagocytosis, quantitative protein iodination, and Staphylococcus killing.
- Compared methotrexate's effects with those of folic acid and folinic acid.
Main Results:
- Methotrexate decreased PMN phagocytosis, protein iodination, and staphylococcal killing in a dose-dependent manner.
- Observed effects were rapid and reversible upon washing, indicating a cell membrane interaction.
- Folic acid and folinic acid did not impair bacterial phagocytosis, suggesting methotrexate specificity.
Conclusions:
- Methotrexate impairs critical PMN functions essential for antibacterial defense.
- The rapid, reversible effects suggest a cell membrane-associated mechanism of action.
- Achievable in vivo concentrations of methotrexate may compromise host antibacterial defenses in patients undergoing therapy.