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 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.
Shen
X
X
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
Hong
F
F
Nguyen
V A
VA
Gao
B
B
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D016898:Interferon-alpha / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D018123:Receptors, Interleukin / Q000235:genetics; D053701:Receptors, Interleukin-10; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D016207:Cytokines; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D016898:Interferon-alpha; D016753:Interleukin-10; D008156:Luciferases; D011506:Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014443:Tyrosine; C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C491409:Socs2 protein, mouse; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse