Modulation of Inflammatory Peritoneal Cell Function and Metabolism by Methotrexate

Abstract Methotrexate (MTX) is widely used in cancer chemotherapy, altnough the effects of MTX on cellular antitumor defense mechanisms are poorly understood. To evaluate the effect of MTX on the cellular inflammatory response, male Sprague-Dawley rats were treated with four daily i.p. injections of MTX or a control vehicle. Kats treated with daily doses of 1.2 mg/kg MTX demonstrated a significant reduction in number of peritoneal exudate cells, specifically macrophages, collected 96 hours following the inflammatory stimulus. To determine if metabolic perturbations also occur upon exposure to LTX, glucose oxidation and protein synthesis by inflammatory cells were monitored in vitro. At a MTX concentration of 10−3M, peritoneal exudate cell 14C-1-glucose and 14C-6-glucose oxidation was significantly depressed. 14C-1-leucine incorporation into TCA precipitable protein was inhibited at 4 × 10−3M MTX. Peritoneal exudate cell viability was not altered at these concentrations of MTX. These results demonstrate that MTX, at therapeutic concentrations, can depress the influx of macrophages to an inflammatory site and also diminish energy metabolism and protein synthesis by inflammatory cells.