title: PD-1 negatively regulates interleukin-12 expression by limiting STAT-1 phosphorylation in monocytes/macrophages during chronic hepatitis C virus infection.
abstract: 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.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Cheng J
authors.initials: CJ
authors.lastname: Ma
authors.forename: Lei
authors.initials: L
authors.lastname: Ni
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: C L
authors.initials: CL
authors.lastname: Zhang
authors.forename: Xiao Y
authors.initials: XY
authors.lastname: Wu
authors.forename: Antwan N
authors.initials: AN
authors.lastname: Atia
authors.forename: Penny
authors.initials: P
authors.lastname: Thayer
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Moorman
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism*; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D018664:Interleukin-12