Abnormal B‐cell activation associated with TALL‐1 over‐expression and SOCS‐1 suppression during chronic hepatitis C virus infection

Moorman, Jonathan P.; Dong, Zhi P; Ni, Lei; Zhang, Chunlan; Borthwick, Thomas; Yao, Zhi Q.

doi:10.1111/j.1365-2567.2009.03106.x

Cited by 24 publications

(33 citation statements)

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“…Another associated disease, known as non-Hodgkin lymphoma, results directly from aberrant B cell proliferation (70). As previously mentioned, SOCS1 is decreased in B cells taken from HCV-infected patients (39) or those incubated with HCV core protein in vitro (74). Decreased SOCS1 expression correlates with increased STAT1 activation and with increases in both B cell proliferation and IgM/IgG production.…”

Section: Effects Of Socs Expression On Viral Diseasementioning

confidence: 75%

“…This is accompanied by decreases in STAT1 activation, markers of general T cell activation, and JAK/STAT-mediated IFN-␥ production, a response which greatly impedes the ability of CTLs to effectively clear viruses and promotes chronic HCV infection. In contrast, HCV core protein decreases the levels of SOCS1 in B cells (39,74). This decrease correlates with increased STAT1 activation and markers of general B cell activation, as well as increased B cell proliferation and antibody (IgM and IgG) production.…”

Section: Virally Exploited Functions Of Socs Proteinsmentioning

confidence: 94%

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Viral Exploitation of Host SOCS Protein Functions

Akhtar

Benveniste

2011

J Virol

110

102

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Over the past decade, a family of host proteins known as suppressors of cytokine signaling (SOCS) have emerged as frequent targets of viral exploitation. Under physiologic circumstances, SOCS proteins negatively regulate inflammatory signaling pathways by facilitating ubiquitination and proteosomal degradation of pathway machinery. Their expression is tightly regulated to prevent excessive inflammation while maintaining protective antipathogenic responses. Numerous viruses, however, have developed mechanisms to induce robust host SOCS protein expression following infection, essentially "hijacking" SOCS function to promote virus survival. To date, SOCS proteins have been shown to inhibit protective antiviral signaling pathways, allowing viruses to evade the host immune response, and to ubiquitinate viral proteins, facilitating intracellular viral trafficking and progeny virus assembly. Importantly, manipulation of SOCS proteins not only facilitates progression of the viral life cycle but also powerfully shapes the presentation of viral disease. SOCS proteins can define host susceptibility to infection, contribute to peripheral disease manifestations such as immune dysfunction and cancer, and even modify the efficacy of therapeutic interventions. Looking toward the future, it is clear that a better understanding of the role of SOCS proteins in viral diseases will be essential in our struggle to modulate and even eliminate the pathogenic effects of viruses on the host.

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Section: Effects Of Socs Expression On Viral Diseasementioning

confidence: 75%

Section: Virally Exploited Functions Of Socs Proteinsmentioning

confidence: 94%

Viral Exploitation of Host SOCS Protein Functions

Akhtar

Benveniste

2011

J Virol

110

102

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“…PD-1 and SOCS-1 were also shown to regulate murine monocyte IL-10/IL-12 production against bacterial infection (23)(24)(25)(26). Similarly, we demonstrated that HCV core protein, by interaction with a complement receptor (gC1qR), can differentially regulate T and B lymphocyte functions through modulating PD-1/SOCS-1 signaling (27)(28)(29)(30)(31)(32). Little is known about the role of these two negative modulators in human innate immune cells, such as M/M F s, in HCV infection.…”

mentioning

confidence: 80%

“…For detection of phosphorylated proteins, the membrane was probed with anti-phospho-STAT-1 (Tyr701), MAPK p38 (Thr 180/182), and total STAT or MAPK Ab (Cell Signaling Technology, Danvers, MA). The HRP secondary Ab incubation, signal development, and data process were carried out as described previously (28). HCV core/gC1qR or PD-1/PDL-1 blockade Primary M/M F s from healthy subjects or HCV patients or monocytic THP-1 cells were incubated with 10 ml anti-gC1qR (1:10 dilution, blocking Ab was generously provided by Dr. Young S. Hahn, University of Virginia), 10 mg/ml anti-PD1 or anti-PDL-1, or control IgG Abs (eBioscience, San Diego, CA) overnight, followed by stimulation with LPS and R848 in the presence or absence of HCV core protein for 18-72 h; IL-12/PD-1/SOCS-1 expression in the treated cells was detected as described.…”

Section: Western Blotting and Coimmunoprecipitationmentioning

confidence: 99%

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

Zhang

Cheng

et al. 2011

The Journal of Immunology

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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/MΦs) 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/MΦs. We analyzed TLR-stimulated, primary CD14+ M/MΦs 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/MΦs from HCV-infected subjects at baseline exhibited comparatively increased PD-1 expression that significantly correlated with the degree of IL-12 inhibition. M/MΦs 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/MΦ led to activation of STAT-1 during TLR-stimulated IL-12 production. These data suggested that HCV core/gC1qR engagement on M/MΦs 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.

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“…HCV infection is associated not only with liver diseases, but also numerous hematologic, renal, dermatologic, rheumatic, and autoimmune disorders, including arthalgia, arthritis, vasculitis, Sicca syndrome, myalgia, and fibromyalgia (Buskila, 2009). The persistence of HCV in lymphocytes causes their oligoclonal and monoclonal proliferation, the appearance of non-organ-specific autoantibodies, and leads to autoimmune Type II mixed cryoglobulinemia and development of several types of indolent non-Hodgkin's lymphomas (de Re et al, 2009;Moorman et al, 2009;Atta et al, 2010).…”

Section: R E S E a R C H A R T I C L Ementioning

confidence: 99%