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

FEBS Lett. 2000 Sep 1;480(2-3):132-6. doi: 10.1016/s0014-5793(00)01905-0.

Abstract

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 levels of IL-10 are poorly responsive to IFN-alpha. The mechanism underlying such controversial functions of IL-10 remains unknown. Here we demonstrated that injection of IL-10 into mice attenuated IFN-alpha-induced signal transducer and activator transcription factor (STAT)1 tyrosine phosphorylation in the liver. Reverse transcriptase-polymerase chain reaction assay demonstrated 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 but not STAT1 tyrosine phosphorylation and induced suppressor of cytokine signal 2 (SOCS2), SOCS3, and cytokine-inducible SH2 protein (CIS) mRNA expression in the liver. Furthermore, overexpression of SOCS2 or SOCS3 inhibited IFN-alpha-induced reporter activity in hepatic cells. These findings suggest that IL-10 inhibits IFN-alpha-activated STAT1 in the liver, at least in part, 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 cautious.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / metabolism
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression
  • Genes, Reporter
  • Humans
  • Immediate-Early Proteins / genetics
  • Interferon-alpha / metabolism*
  • Interleukin-10 / metabolism*
  • Liver / metabolism*
  • Luciferases / genetics
  • Mice
  • Mice, Inbred ICR
  • Phosphorylation
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA, Messenger
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin-10
  • Repressor Proteins*
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Signal Transduction
  • Spleen / metabolism
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / metabolism*
  • Transcription Factors*
  • Tyrosine / metabolism
  • src Homology Domains

Substances

  • Cytokines
  • DNA-Binding Proteins
  • Immediate-Early Proteins
  • Interferon-alpha
  • Proteins
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Interleukin-10
  • Repressor Proteins
  • SOCS2 protein, human
  • SOCS3 protein, human
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Socs2 protein, mouse
  • Socs3 protein, mouse
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • cytokine inducible SH2-containing protein
  • Interleukin-10
  • Tyrosine
  • Luciferases