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Expression of a COX-2 Transgene in Murine Liver Causes Hepatitis
  1. Jun Yu (junyu{at}cuhk.edu.hk)
  1. Chinese University of Hong Kong, Hong Kong
    1. Alex Y Hui
    1. Chinese University of Hong Kong, Hong Kong
      1. Eagle SH Chu
      1. Chinese University of Hong Kong, Hong Kong
        1. Alfred SL Cheng
        1. Chinese University of Hong Kong, Hong Kong
          1. Minnie YY Go
          1. Chinese University of Hong Kong, Hong Kong
            1. Henry LY Chan
            1. Chinese University of Hong Kong, Hong Kong
              1. Wai K Leung
              1. Chinese University of Hong Kong, Hong Kong
                1. Kin F Cheung
                1. Chinese University of Hong Kong, Hong Kong
                  1. Arthur KK Ching
                  1. Chinese University of Hong Kong, Hong Kong
                    1. Yiu L Chui
                    1. Chinese University of Hong Kong, Hong Kong
                      1. Ka K Chan
                      1. Chinese University of Hong Kong, Hong Kong
                        1. Joseph JY Sung
                        1. Chinese University of Hong Kong, Hong Kong

                          Abstract

                          Background: It has been proven that cyclooxygenase-2 (COX-2) is rapidly induced by inflammatory mediators. However, it is not known if overexpression of COX-2 in liver is sufficient to promote activation or secretion of inflammatory factors leading to hepatitis.

                          Aim: We investigated the role of COX-2 forced expression in liver by using inducible COX-2 transgenic (TG) mice.

                          Methods: TG mice that overexpress the human COX-2 gene in the liver using the liver specific transthyretin (TTR) promoter and non-TG littermates were derived and fed the normal diet for up to 12 months. Hepatic prostaglandin E2 (PGE2) content was determined by enzyme immunoassay, NF-κB activation by Electrophoretic Mobility Shift Assays (EMSA), apoptosis by TUNEL and proliferation by ki-67 immunohistochemistry.

                          Results: COX-2 TG mice exhibited strongly increased COX-2 and PGE2, elevated serum ALT level and histologic hepatitis. Hepatic COX-2 expression in the TG mice resulted in activation of NF-κB and inflammatory cytokine cascade with marked expression of the pro-inflammatory cytokines TNF-α (9.4-fold), IL-6 (4.4-fold), IL-1β (3.6-fold) and of the anti-inflammatory cytokine IL-10 (4.4-fold) as well as chemokine MIP-2 (3.2-fold). The inflammatory response of the COX-2 TG mice was associated with macrophage and lymphocytes infiltration, increased cell proliferation and high rates of cell apoptosis. Administration of the COX-2 inhibitor celecoxib in TG mice restored liver histology to normal.

                          Conclusion: Enhanced COX-2 expression in hepatocytes is sufficient to induce hepatitis by activating of NF-κB, stimulating the secretion of pro-inflammatory cytokines, recruiting macrophage and altering cell kinetics. Inhibition of COX-2 represent a mechanism-based chemopreventive approach for hepatitis.

                          • cell kinetics
                          • cyclooxygenase-2
                          • hepatitis
                          • inflammatory factors
                          • transgenic mouse model

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