Woodchuck gamma interferon upregulates major histocompatibility complex class I transcription but is unable to deplete woodchuck hepatitis virus replication intermediates and RNAs in persistently infected woodchuck primary hepatocytes

Gamma interferon (IFN-gamma) is an important mediator with multiple functio ns in the host defense against viral infection. IFN-gamma, in concert with tumor necrosis factor alpha (TNF-alpha), leads to a remarkable reduction of intrahepatic replication intermediates and specific mRNAs of hepatitis B v irus (HBV) by a noncytolytic mechanism in the transgenic mouse model. Thus, it is rational to evaluate the potential value of IFN-gamma for the treatm ent of chronic HBV infection. In the present study, we expressed recombinan t woodchuck IFN-gamma (wIFN-gamma) in Escherichia coli and mammalian cells. wIFN-gamma protected woodchuck cells against infection of murine encephalo myocarditis virus in a species-specific manner. It upregulated the mRNA lev el of the woodchuck major histocompatibility complex class I (MHC-I) heavy chain in permanent woodchuck WH12/6 cells and regulated differentially the gene expression. However, the level of the replication intermediates and sp ecific RNAs of woodchuck hepatitis virus (WHV) in persistently WHV-infected primary woodchuck hepatocytes did not change despite a treatment with 1,00 0 U of wIFN-gamma per ml or with a combination of wIFN-gamma and woodchuck TNF-alpha. Rather, hepatocytes derived from chronic carriers had an elevate d level of the MHC-I heavy-chain mRNAs, most probably due to the exposure t o inflammatory cytokines in vivo. Treatment with high doses of wIFN-gamma l ed to an abnormal cell morphology and loss of hepatocytes. Thus, wIFN-gamma regulates the gene expression in woodchuck hepatocytes but could not deple te WHV replication intermediates and mRNAs in persistently infected hepatoc ytes. The cellular response to wIFN-gamma may be changed in hepatocytes fro m chronically WHV-infected woodchucks. It should be clarified in the future whether the continuous exposure of hepatocytes to inflammatory cytokines o r the presence of viral proteins leads to changes of the cellular response to wIFN-gamma.