Article Text

other Versions

Interferon gamma inhibits interleukin-1-induced MMP-13 expression in human articular chondrocytes via receptor- mediated STAT-1 activation and interaction with CBP/P300 coactivator
  1. R Ahmad
  1. Hopital Notre-Dame du CHUM, Canada
    1. H Y Qureshi
    1. Hopital Notre-Dame du CHUM, Canada
      1. M El Mabrouk
      1. Hopital Notre-Dame du CHUM, Canada
        1. J Sylvester
        1. Hopital Notre-Dame du CHUM, Canada
          1. M Ahmad
          1. Emory University, Atlanta, United States
            1. M Zafarullah (muhammad.zafarullah{at}
            1. Hopital Notre-Dame du CHUM, Canada


              Background: Despite well-documented immunomodulation by interferon gamma (IFN-γ), its role and mechanism of regulation of matrix metalloproteinase-13 (MMP-13) gene expression in human chondrocytes is unknown.

              Objective: To investigate the ability and mechanism of IFN-γ to suppress interleukin-1 (IL- 1)-induced MMP-13 expression in articular chondrocytes.

              Methods: Human chondrocytes were treated with IFN- γ or IL-1β alone or in combination. MMP-13 mRNA was analyzed by semi-quantitative RT-PCR. MMP-13 protein, phospho-STAT1 and p44/42 MAPK levels were measured by Western blotting. MMP-13 promoter- luciferase, CMV-CBP/p300 plasmids and STAT1 siRNA were transfected by Calcium phosphate method. IFN-γ receptor was also neutralized. AP-1 activity was monitored by TransAM transcription factor kit. STAT1- CBP/p300 interaction was studied by immunoprecipitation.

              Results: IFN-γ potently suppressed IL-1- induced expression of MMP-13 and promoter activity. Blockade with neutralizing IFN-γR1 antibody revealed that MMP-13 inhibition by IFN-γ was mediated by the IFN receptor. IFN-β-stimulated activation of STAT1 was directly correlated with MMP-13 suppression. Knockdown of STAT1 gene by specific siRNA or its inhibition with Fludarabine partially restored the IL-1 induction of MMP-13 expression and promoter activity. IFN-γ did not alter activator protein (AP-1) binding ability but promoted physical interaction of STAT1 and CBP/p300 co-activator. P300 overexpression reversed IFN-γ inhibition of endogenous MMP-13 mRNA expression and exogenous MMP-13 promoter activity.

              Conclusion: IFN-γ through its receptor activates STAT1, which binds with CBP/p300 co-activator, sequesters it from the cell system and thus inhibits transcriptional induction of MMP-13 gene in chondrocytes. IFN-γ and its signaling pathways could be targeted therapeutically for diminishing IL-1- induced cartilage degradation by MMP-13 in patients with arthritis.

              • MMP-13,
              • STAT1
              • arthritis
              • chondrocytes
              • interferon gamma,

              Statistics from

              Request permissions

              If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.