Inhibition of human granulocyte function by methotrexate

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.