PD-1 Negatively Regulates Interleukin-12 Expression by Limiting Stat-1 Phosphorylation in Monocytes/Macrophages During Chronic Hepatitis C Virus Infection
Document Type
Article
Publication Date
3-1-2011
Description
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. No claim to original US government works.
Citation Information
Ma, Cheng J.; Ni, Lei; Zhang, Ying; Zhang, C. L.; Wu, Xiao Y.; Atia, Antwan N.; Thayer, Penny; Moorman, Jonathan P.; and Yao, Zhi Q.. 2011. PD-1 Negatively Regulates Interleukin-12 Expression by Limiting Stat-1 Phosphorylation in Monocytes/Macrophages During Chronic Hepatitis C Virus Infection. Immunology. Vol.132(3). 421-431. https://doi.org/10.1111/j.1365-2567.2010.03382.x PMID: 21091911 ISSN: 0019-2805