IL-10 attenuates IFN-alpha-activated STAT1 in the liver: involvement of SOCS2 and SOCS3

Interleukin-10 (IL-10) has been used in the treatment of viral hepatitis in interferon-alpha (IFN-alpha) non-responders while patients who have high l evels of IL-10 are poorly responsive to IFN-alpha, The mechanism underlying such controversial functions of IL-10 remains unknown, Here we demonstrate d that injection of IL-10 into mice attenuated IFN-alpha-induced signal tra nsducer and activator transcription factor (STAT)1 tyrosine phosphorylation in the liver. Reverse transcriptase-polymerase chain reaction assay demons trated that mouse liver expressed high levels of IL-10 receptor 2 (IL-10R2) but low levels of IL-10R1. Injection of IL-10 into mice activated STAT3 bu t not STAT1 tyrosine phosphorylation and induced suppressor of cytokine sig nal 2 (SOCS2), SOCS3, and cytokine-inducible SH2 protein (CIS) mRNA express ion in the liver. Furthermore, overexpression of SOCS2 or SOCS3 inhibited I FN-alpha-induced reporter activity in hepatic cells. These findings suggest that IL-10 inhibits IFN-alpha-activated STAT1 in the liver, at least in pa rt, by inducing SOCS2, SOCS3, and CIS expression, which may be responsible for the resistance of IFN-alpha therapy in patients who have high levels of IL-10 and recommends that IL-10 treatment for viral hepatitis should be ca utious. (C) 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.