Suppressor of cytokine signaling (SOCS)-3 gene transfer protects against collagen-induced arthritis

Background

Rheumatoid arthritis is characterized by an acute phase response of the liver. IL-6 is produced in the inflamed joint and high levels are found in the circulation. IL-6 is a potent inducer of acute-phase proteins (APP) in hepatocytes via its signal transducer gp130 by the activation of the signal transducer and activator of transcription (STAT)-3.

Objective

The aim of the study was to determine the effect of adenoviral gene transfer of SOCS-3, the inhibitor of STAT3 activation, on collagen-induced arthritis (CIA).

Methods

Livers were dissected, and activation of STATs was analyzed by Western blot and gene expression by RT-PCR. A replication incompetent adenovirus containing the gene of murine SOCS-3 was constructed. Mice received 3 × 10e8 ffu of Ad5.CMV.mSOCS3 or control viruses intravenously before onset of arthritis. The effect of SOCS gene transfer on liver function was studied in zymosan-induced gonarthritis (ZIA) and the therapeutic effect in CIA.

Results

Induction of ZIA in the knee joints of mice caused a rapid (within 5 hours) activation of STAT3 but not STAT1 in the liver. The activation of STAT3 was IL-6 dependent, as shown using IL-6 gene knockout mice. Intravenous injection of Ad5.CMV.mSOCS3 24 hours before induction of ZIA prevented STAT3 activation and markedly reduced serum amyloid A (SAA)-1 gene expression in the liver. Control virus treatment did not inhibit STAT3 activation in the liver. Overexpression of SOCS-3 did not affect Erk activation, confirming selectivity for the STAT signaling pathway. Treatment of DBA1/j mice with Ad5.CMV.mSOCS3 virus after immunization ameliorated CIA, and reduced serum TNF-α levels accompanied this effect. SOCS-3 treatment had no effect on the circulating levels of total IgG, IgG_2a and IgG₁ anti-collagen type II antibodies.

Conclusion

Inhibition of STAT-mediated signaling via SOCS-3 adenoviral gene transfer in the liver markedly ameliorated CIA. This suggests that the IL-6 mediated liver response modulates the development of arthritis.