Type I and III interferons enhance IL-10R expression on human monocytes and macrophages, resulting in IL-10-mediated suppression of TLR-induced IL-12.
Currently, only about 30-50% of chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) patients respond to IFN-based therapy. It has been suggested that IL-10 is involved in suppressing the activity of type I IFNs on antigen-presenting cells (APCs). However, the interaction between type I IFNs and IL-10 is still not clear. Here we report that IFN-α priming upregulated the expression of IL-10R1 on monocytes, and subsequently IL-10 induced a higher level of STAT3 phosphorylation in IFN-primed cells. This indicates that IFN-α increased the sensitivity of monocytes to IL-10, and as a result, TLR-induced IL-12p70 by IFN-pretreated cells was suppressed. Interestingly, both IFN-β and IL-29, a member of the type III IFN family, comparably sensitized monocytes and macrophages to IL-10 stimulation, indicating a general effect of IFN on the activity of IL-10 in APCs. In summary, we demonstrate that one of the consequences of priming human APCs with IFN is to promote the cells' sensitivity to IL-10, which leads to the inhibition of TLR-induced IL-12p70 production. Therefore, type I and III IFNs induce a suboptimal activation of immune cells. These findings are relevant for the development of strategies to further improve IFN-based therapy for patients with multiple sclerosis or viral hepatitis.
Liver Unit, Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
Bi-Sheng
BS
Liu
Harry L A
HL
Janssen
André
A
Boonstra
D000938:Antigen-Presenting Cells / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D007372:Interferons; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D053709:Interleukin-10 Receptor alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000095022:Interferon Lambda
D007370:Interferon Type I; D016899:Interferon-beta; D007372:Interferons; D016753:Interleukin-10; D053709:Interleukin-10 Receptor alpha Subunit; D018664:Interleukin-12; D007378:Interleukins; D050796:STAT3 Transcription Factor; D051193:Toll-Like Receptors; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494086:STAT3 protein, human