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Estrogens inhibit interleukin-1β-mediated nitric oxide synthase expression in articular chondrocytes through NF-κB impairment.
  1. Pascal Richette (pascal.richette{at}
  1. INSERM-UMR-747, France
    1. Marie-France Dumontier (marie-france.dumontier{at}
    1. INSERM-UMR-747, France
      1. Khadija Tahiri (khadija.tahiri{at}
      1. INSERM-UMR-747, France
        1. Magdalena Widerak (mangusta{at}
        1. INSERM-UMR-747, France
          1. Antoine Torre (antoinetorre{at}
          1. INSERM-UMR-747, France
            1. Mourad Benallaoua (mourad.benallaoua{at}
            1. INSERM-UMR-747, France
              1. François Rannou (francois.rannou{at}
              1. INSERM-UMR-747, France
                1. Marie-Thérèse Corvol (maite.corvol{at}
                1. INSERM-UMR-747, France
                  1. Jean-François Savouret (jean-francois.savouret{at}
                  1. INSERM-UMR-747, France


                    Objectives: To investigate the presence and functionality of estrogen receptor alpha (ERα) in IL-1β-treated rabbit articular chondrocytes in culture. To determine the mechanisms of 17β estradiol (E2) effects on IL-1β-induced iNOS expression.

                    Methods: The presence and functionality of ER& [alpha] were investigated by immunocytochemistry and transient expression of an E2-responsive reporter construct. iNOS expression and production were determined by transient expression of a chimeric iNOS promoter-luciferase construct and protein immunoblotting. NO production was determined by the Griess reaction. DNA binding activities of NF-kB and AP- 1 were determined by EMSA-Elisa assays. Nuclear translocation of p65 was studied by immunocytochemistry.

                    Results: ERα was identified in the nucleus of chondrocytes. ERα efficiently transactivated a transiently expressed E2-responsive construct. Upon IL-1& [beta] treatment, ERα partially diffused from its nuclear localisation into the cytoplasm and its transactivation ability was impaired. Nevertheless, E2, Tamoxifen and Raloxifene efficiently inhibited IL-1& [beta] induced NO production (- 34%, - 31% and - 36% respectively). E2 decreased IL-1β induced iNOS protein expression (- 40%). Transient expression of an iNOS promoter construct strongly suggested that iNOS expression was inhibited at the transcriptional level and EMSA-ELISA assays showed that E2 reduced (- 60%) the IL-1β induced p65 DNA binding capacity. Finally, the p65 nuclear translocation induced by IL-1β was also strongly decreased by E2.

                    Conclusions: Our data support a reciprocal antagonism between estrogens and IL-1β ultimately resulting in the decrease of cytokine-dependent NO production through transcriptional inhibition of iNOS expression. This effect was associated with selective inhibition of p65 DNA binding and nuclear translocation.

                    • cartilage
                    • chondrocytes
                    • estrogens
                    • interleukin-1
                    • selective estrogen receptor modulators

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                    • The name of Mourad Benallaoua is misspelled : "Benallaloua" appears instead of "Benallaoua", both in the authors list and in the authors affiliations list.

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                        BMJ Publishing Group Ltd and European League Against Rheumatism