Paradoxical enhancement of interleukin-2-mediated cytotoxicity against K562 cells by addition of a low dose of methotrexate.
In vitro effects of methotrexate (MTX) on interleukin-2(IL-2)-mediated cytotoxicity of peripheral blood mononuclear cells (PBMC) were studied. PBMC were incubated with human recombinant IL-2 (25 U/ml) for 72 h; during the last 24 h, various concentrations (10 pM-1 microM) of MTX were added to the culture. Cytotoxicity against k562 cells was measured by a 4-h 51Cr-release assay. The IL-2-mediated cytotoxicity was paradoxically increased at around a concentration (10 nM) MTX. Such a low concentration of MTX showed no anti-proliferative effect on cell growth. This enhancement with 10 nM MTX was shown only in an E-rosette+ (E+) population, but not in E-rosette- (E-). In addition, when E+ cells were treated with an anti-CD16 monoclonal antibody plus complement after incubation with IL-2 and MTX, MTX-induced enhancement was lost, suggesting that an E+CD16+ cell population was mainly involved in this augmentation. Positively sorted E+CD16+ cells showed similar enhancement of cytotoxicity after treatment with IL-2 plus MTX. On the other hand, MTX treatment did not show the phenotypical changes including of the E+CD16+ cells, indicating that this treatment did not affect the differentiation and proliferation of the specific cell subset. Our results indicate that a low dose of MTX could have a role in the regulation of immunological anti-cancer surveillance systems through the natural killer and lymphokine-activated cytotoxic cells.
Nakarai
T
T
Department of Pediatrics, Kanazawa University School of Medicine, Japan.
Ueno
Y
Y
Ueno
Y
Y
Koizumi
S
S
D000328:Adult; D000943:Antigens, Differentiation / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007376:Interleukin-2 / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007942:Leukemia, Experimental / Q000188:drug therapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology*; D010641:Phenotype; D011961:Receptors, Fc / Q000276:immunology; D017452:Receptors, IgG; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000943:Antigens, Differentiation; D007376:Interleukin-2; D011961:Receptors, Fc; D017452:Receptors, IgG; D008727:Methotrexate