Antiproliferative-antiinflammatory effects of methotrexate and sex hormones on cultured differentiating myeloid monocytic cells (THP-1).
Methotrexate (MTX) is believed to exert both antiproliferative and antiinflammatory effects in a dose-related manner in a majority of rheumatoid arthritis (RA) patients along with an abrupt flare of the disease after drug discontinuation. To investigate the antiproliferative and antiinflammatory actions of MTX and the combined action of sex hormones, we evaluated these effects in differentiated monocytic myeloid cells (THP-1) prestimulated with testosterone (T) or 17-beta estradiol (E2). The effects of MTX and T combined treatment (T/MTX) on THP-1 cells showed a significant inhibition of cell proliferation when compared with E2/MTX- treated cells or controls: 53% at 72 h versus E2-treated cells; 58% at 96 h versus E2-treated cells; and 41% versus controls, respectively. Bax and Fas CD95 expression was found increased in T-treated cells: 14% T at 48 h vs. E(2)-treated cells and controls; 45% T at 72 h versus E2-treated cells and controls; 97% at 96 h versus E2-treated cells and 37% versus controls for Bax: 33%, 41%, and 42% T versus E2-treated cells for Fas. Moreover, a significant decrease of IL-12 levels in T/MTX treated cells was found at any time when compared to E2-treated cells. In summary, the association of testosterone and MTX compared to MTX alone suggests possible synergistic actions. Therefore, the enhancing antiinflammatory effects exerted by androgens might represent a further explanation for the reduced frequency of inflammatory diseases in male subjects.
Laboratory and Division of Rheumatology, Department of Internal Medicine and Medical Specialities, University of Genova, Genova, Italy. mcutolo@unige.it
Maurizio
M
Cutolo
Alberto
A
Sulli
Chiara
C
Craviotto
Lamberto
L
Felli
Carmen
C
Pizzorni
Bruno
B
Seriolo
Barbara
B
Villaggio
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D004958:Estradiol / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D013739:Testosterone / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; C494826:BAX protein, human; D006131:Growth Inhibitors; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D013739:Testosterone; D004958:Estradiol; D007371:Interferon-gamma; D008727:Methotrexate