Upregulation of SOCS-3 and PIAS-3 impairs IL-12-mediated interferon-gamma response in CD56 T cells in HCV-infected heroin users.
BACKGROUND
CD56(+) T cells are abundant in liver and play an important role in host innate immunity against viral infections, including hepatitis C virus (HCV) infection, a common infection among heroin abusers. We thus investigated the in vivo impact of heroin use or heroin use plus HCV infection on the CD56(+) T cell frequency and function.


RESULTS
A total of 37 heroin users with (17) or without (20) HCV infection and 17 healthy subjects were included in the study. Although there was no significant difference in CD56(+) T cell frequency in PBMCs among three study groups, CD56(+) T cells isolated from the heroin users had significantly lower levels of constitutive interferon-gamma (IFN-gamma) expression than those from the normal subjects. In addition, when stimulated by interleukin (IL)-12, CD56(+) natural T cells from HCV-infected heroin users produced significantly lower levels of IFN-gamma than those from the normal subjects. This diminished ability to produce IFN-gamma by CD56(+) T cells was associated with the increased plasma HCV viral loads in the HCV-infected heroin users. Investigation of the mechanisms showed that although heroin use or heroin use plus HCV infection had little impact on the expression of the key positive regulators (IL-12 receptors, STAT-1, 3, 4, 5, JAK-2, and TYK-2) in IL-12 pathway, heroin use or heroin use plus HCV infection induced the expression of suppressor of cytokine signaling protein-3 (SOCS-3) and protein inhibitors of activated STAT-3 (PIAS-3), two key inhibitors of IL-12 pathway.


CONCLUSIONS
These findings provide compelling in vivo evidence that heroin use or heroin use plus HCV infection impairs CD56(+) T cell-mediated innate immune function, which may account for HCV infection and persistence in liver.
Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Li
L
Ye
Xu
X
Wang
David S
DS
Metzger
Eric
E
Riedel
Luis J
LJ
Montaner
Wenzhe
W
Ho
D019002:CD56 Antigen / Q000096:biosynthesis*; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000378:metabolism; D006526:Hepatitis C / Q000150:complications*; D003932:Heroin; D006556:Heroin Dependence; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008099:Liver / Q000821:virology; D018832:Molecular Chaperones / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology*; D015854:Up-Regulation
D019002:CD56 Antigen; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018664:Interleukin-12; D003932:Heroin; D007371:Interferon-gamma