Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation.
Hepatitis C virus (HCV) is remarkably efficient at establishing persistent infection, suggesting that it has evolved one or more strategies aimed at evading the host immune response. T cell responses, including interferon-gamma production, are severely suppressed in chronic HCV patients. The HCV core protein has been previously shown to circulate in the bloodstream of HCV-infected patients and inhibit host immunity through an interaction with gC1qR. To determine the role of the HCV core-gC1qR interaction in modulation of inflammatory cytokine production, we examined interleukin (IL)-12 production, which is critical for the induction of interferon-gamma synthesis, in lipopolysaccharide-stimulated human monocyte/macrophages. We found that core protein binds the gC1qR displayed on the cell surface of monocyte/macrophages and inhibits the production of IL-12p70 upon lipopolysaccharide stimulation. This inhibition was found to be selective in that HCV core failed to affect the production of IL-6, IL-8, IL-1beta, and tumor necrosis factor alpha. In addition, suppression of IL-12 production by core protein occurred at the transcriptional level by inhibition of IL-12p40 mRNA synthesis. Importantly, core-induced inhibition of IL-12p40 mRNA synthesis resulted from impaired activation of AP-1 rather than enhanced IL-10 production. These results suggest that the HCV core-gC1qR interaction may play a pivotal role in establishing persistent infection by dampening TH1 responses.
Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville 22908, USA.
Audrey L
AL
Eisen-Vandervelde
Stephen N
SN
Waggoner
Zhi Qiang
ZQ
Yao
Evan M
EM
Cale
Chang S
CS
Hahn
Young S
YS
Hahn
D002478:Cells, Cultured; D016174:Hepacivirus; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000235:genetics*; D007378:Interleukins / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014758:Viral Core Proteins / Q000502:physiology*
D007378:Interleukins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014758:Viral Core Proteins; D018664:Interleukin-12