title: Estrogens interfere with leflunomide modulation of cytokine production by human activated monocytes.
abstract: Rheumatoid arthritis (RA) prevalence is greater in females than in males, supporting estrogens as modulators of immune response. Leflunomide (LEF) is employed in the RA treatment. We studied the combinatory effects of LEF active metabolite A77 1726 (LEF-M) and 17beta-estradiol (E2) on inflammatory cytokine production by cultured macrophages obtained from activated human monocytes (THP-1 cells). Macrophages were cultured with LEF-M alone and in combination with E2. IL-6, TNF-alpha, and TGF-beta were evaluated by immunocytochemistry (ICC), Western blot (WB), and reverse transcriptase-polymerase chain reaction (RT-PCR). ICC, as well as WB and RT-PCR, showed that LEF-M, in respect to untreated cells, significantly downregulated the cytokine production (IL-6 P < 0.01, TNF-alphaP < 0.001, TGF-betaP < 0.01). On the contrary, E2 increased the cytokine production, a result that was significantly reversed when LEF-M was subsequently added (IL-6, TNF-alpha, TGF-betaP < 0.001 vs. E2). E2 seems to contrast the LEF-M activity. These results might support a more efficient therapeutical effect of LEF in male with respect to female RA patients.
authors.affiliation: Research Laboratories and Clinical Academic Unit of Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Montagna
authors.forename: Stefano
authors.initials: S
authors.lastname: Soldano
authors.forename: Renata
authors.initials: R
authors.lastname: Brizzolara
authors.forename: Barbara
authors.initials: B
authors.lastname: Villaggio
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Triolo
authors.forename: Paolo
authors.initials: P
authors.lastname: Clerico
authors.forename: Marianna
authors.initials: M
authors.lastname: Meroni
authors.forename: Alberto
authors.initials: A
authors.lastname: Sulli
authors.forename: Bruno
authors.initials: B
authors.lastname: Seriolo
authors.forename: Luigi
authors.initials: L
authors.lastname: Molfetta
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cutolo
mesh_terms: D000814:Aniline Compounds / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003437:Crotonates; D016207:Cytokines / Q000096:biosynthesis*; D004347:Drug Interactions; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006885:Hydroxybutyrates / Q000378:metabolism; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000096:biosynthesis; D007555:Isoxazoles / Q000494:pharmacology*; D000077339:Leflunomide; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D009570:Nitriles; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014052:Toluidines; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000814:Aniline Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003437:Crotonates; D016207:Cytokines; D004967:Estrogens; D006885:Hydroxybutyrates; D015850:Interleukin-6; D007555:Isoxazoles; D009570:Nitriles; D014052:Toluidines; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C527525:teriflunomide; D004958:Estradiol; D000077339:Leflunomide; D013755:Tetradecanoylphorbol Acetate