Tumor necrosis factor α attenuates interferon-α signaling in the liver:: involvement of SOCS3 and SHP2 and implication in resistance to interferon therapy

Although interferon alpha (IFN-alpha) has been used for a decade to treat viral hepatitis, a disease that affects millions of people worldwide, more than 60% of viral hepatitis patients respond poorly. It has been reported that high levels of tumor necrosis factor alpha (TNF-alpha) correlated highly with resistance to IFN-alpha therapy. Here we demonstrate that injection of TNF-alpha suppresses IFN-alpha signaling and markedly induces expression of suppressor of cytokine signaling 3 (SOCS3) and SH2 containing protein-tyrosine phosphatase 2 (SHP2) in the liver. TNF-alpha induction of SOCS3 and SHP2 remains unchanged while induction of STAT1 protein expression is completely abolished in IL-6-deficient mice. Immunoprecipitation experiments show that injection of TNF-alpha increases SHP2 association with JAKs. Overexpression of SOCS3 and SHP2 inhibits IFN-alpha signaling in hepatic cells. Injection of carbon tetrachloride, which is known to induce TNF-alpha in the liver, attenuates IFN-alpha signaling in the liver. This attenuation is also observed in TNF-alpha receptor II- (TNF-R2-) deficient mice but is markedly diminished in TNF-R1-deficient mice. Taken together, these findings suggest that TNF-alpha may be involved in resistance to IFN-alpha therapy by induction of SOCS3 and SHP2, and they could be therapeutic targets for improving the efficacy of IFN-alpha therapy.