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

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.

• Authors: X Shen, F Hong, V A Nguyen, B Gao
• Journal: FEBS letters (FEBS Lett) Vol. 480 Issue 2-3 Pg. 132-6 (Sep 01 2000) ISSN: 0014-5793 [Print] England
• PMID: 11034314 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

• 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, 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