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Tumor necrosis factor α attenuates interferon‐α signaling in the liver: involvement of SOCS3 and SHP2 and implication in resistance to interferon therapy
Author(s) -
Hong Feng,
Nguyen Van-Anh,
Gao Bin
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0908fje
Subject(s) - socs3 , stat1 , tumor necrosis factor alpha , interferon , cancer research , signal transduction , cytokine , phosphorylation , tyrosine phosphorylation , jak stat signaling pathway , medicine , protein tyrosine phosphatase , immunology , biology , stat3 , tyrosine kinase , microbiology and biotechnology
Although interferon α (IFN‐α) 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 α (TNF‐α) correlated highly with resistance to IFN‐α therapy. Here we demonstrate that injection of TNF‐α suppresses IFN‐α signaling and markedly induces expression of suppressor of cytokine signaling 3 (SOCS3) and SH2 containing protein‐tyrosine phosphatase 2 (SHP2) in the liver. TNF‐α 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‐α increases SHP2 association with JAKs. Overexpression of SOCS3 and SHP2 inhibits IFN‐α signaling in hepatic cells. Injection of carbon tetrachloride, which is known to induce TNF‐α in the liver, attenuates IFN‐α signaling in the liver. This attenuation is also observed in TNF‐α receptor II‐ (TNF‐R2‐) deficient mice but is markedly diminished in TNF‐R1‐deficient mice. Taken together, these findings suggest that TNF‐α may be involved in resistance to IFN‐α therapy by induction of SOCS3 and SHP2, and they could be therapeutic targets for improving the efficacy of IFN‐α therapy.