Cross-talk between programmed death-1 and suppressor of cytokine signaling-1 in inhibition of IL-12 production by monocytes/macrophages in hepatitis C virus infection.
Hepatitis C virus (HCV) dysregulates innate immune responses and induces persistent viral infection. We previously demonstrated that HCV core protein impairs IL-12 expression by monocytes/macrophages (M/M(Φ)s) through interaction with a complement receptor gC1qR. Because HCV core-mediated lymphocyte dysregulation occurs through the negative immunomodulators programmed death-1 (PD-1) and suppressor of cytokine signaling-1 (SOCS-1), the aim of this study was to examine their role in HCV core-mediated IL-12 suppression in M/M(Φ)s. We analyzed TLR-stimulated, primary CD14(+) M/M(Φ)s from chronically HCV-infected and healthy subjects or the THP-1 cell line for PD-1, SOCS-1, and IL-12 expression following HCV core treatment. M/M(Φ)s from HCV-infected subjects at baseline exhibited comparatively increased PD-1 expression that significantly correlated with the degree of IL-12 inhibition. M/M(Φ)s isolated from healthy and HCV-infected individuals and treated with HCV core protein displayed increased PD-1 and SOCS-1 expression and decreased IL-12 expression, an effect that was also observed in cells treated with gC1qR's ligand, C1q. Blocking gC1qR rescued HCV core-induced PD-1 upregulation and IL-12 suppression, whereas blocking PD-1 signaling enhanced IL-12 production and decreased the expression of SOCS-1 induced by HCV core. Conversely, silencing SOCS-1 expression using small interfering RNAs increased IL-12 expression and inhibited PD-1 upregulation. PD-1 and SOCS-1 were found to associate by coimmunoprecipitation studies, and blocking PD-1 or silencing SOCS-1 in M/M(Φ) led to activation of STAT-1 during TLR-stimulated IL-12 production. These data suggested that HCV core/gC1qR engagement on M/M(Φ)s triggers the expression of PD-1 and SOCS-1, which can associate to deliver negative signaling to TLR-mediated pathways controlling expression of IL-12, a key cytokine linking innate and adaptive immunity.
Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Ying
Y
Zhang
Cheng J
CJ
Ma
Lei
L
Ni
Chun L
CL
Zhang
Xiao Y
XY
Wu
Uday
U
Kumaraguru
Chuan F
CF
Li
Jonathan P
JP
Moorman
Zhi Q
ZQ
Yao
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D002450:Cell Communication / Q000276:immunology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor; D011951:Receptors, Complement / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011951:Receptors, Complement; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051193:Toll-Like Receptors; C032402:complement 1q receptor; D018664:Interleukin-12