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
- inflammatory factors
- transgenic mouse model
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