PD-1 negatively regulates interleukin-12 expression by limiting STAT-1 phosphorylation in monocytes/macrophages during chronic hepatitis C virus infection

Immunology. 2011 Mar;132(3):421-31. doi: 10.1111/j.1365-2567.2010.03382.x. Epub 2010 Nov 23.


Hepatitis C virus (HCV) is remarkably efficient at evading host immunity to establish chronic infection. During chronic HCV infection, interleukin-12 (IL-12) produced by monocytes/macrophages (M/Mφ) is significantly suppressed. Programmed death-1 (PD-1), an inhibitory receptor on immune cells, plays a pivotal role in suppressing T-cell responses during chronic viral infection. To determine whether PD-1 regulates IL-12 production by M/Mφ during chronic HCV infection, we examined the expressions of PD-1, its ligand PDL-1, and their relationship with IL-12 production in M/Mφ from HCV-infected, HCV-resolved, and healthy subjects by flow cytometry. Toll-like receptor (TLR) -mediated IL-12 production by M/Mφ was selectively suppressed, while PD-1/PDL-1 expressions were up-regulated, in HCV-infected subjects compared with HCV-resolved or healthy subjects. Up-regulation of PD-1 was inversely associated with the degree of IL-12 inhibition in HCV infection. Interestingly, the reduced response of M/Mφ from HCV-infected individuals to TLR ligands appeared not to be the result of a lack of the ability to sense pathogen, but to an impaired activation of intracellular janus kinase/signal transducer and activator of transfection (STAT) pathway as represented by inhibited STAT-1 phosphorylation in M/Mφ from HCV-infected individuals compared with HCV-negative subjects. Successful HCV treatment with pegylated interferon/ribavirin or blocking PD-1/PDL-1 engagement ex vivo led to reduced PD-1 expression and improved IL-12 production as well as STAT-1 activation in M/Mφ from HCV-infected individuals. These results suggest that the PD-1 inhibitory pathway may negatively regulate IL-12 expression by limiting STAT-1 phosphorylation in M/Mφ during chronic HCV infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antigens, CD / immunology
  • Antigens, CD / metabolism*
  • Apoptosis Regulatory Proteins / immunology
  • Apoptosis Regulatory Proteins / metabolism*
  • Cell Separation
  • Female
  • Flow Cytometry
  • Gene Expression
  • Gene Expression Regulation*
  • Hepatitis C, Chronic / immunology
  • Hepatitis C, Chronic / metabolism*
  • Humans
  • Interleukin-12 / biosynthesis*
  • Interleukin-12 / immunology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Male
  • Middle Aged
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Phosphorylation
  • Programmed Cell Death 1 Receptor
  • STAT1 Transcription Factor / immunology
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction / immunology


  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Interleukin-12