13 The vast majority of these factors activate STAT3, underscoring STAT3 as an important transcription factor in MDSC differentiation. Indeed, ablation of STAT3 using conditional knockout mice reduced the expansion of MDSCs and improved T-cell responses Selleck 3 Methyladenine in tumor-bearing mice.14 MDSCs have been shown to suppress T-cell responses by way of numerous mechanisms including expression of inhibitory cell surface molecules, production of regulatory cytokines, the metabolism of arginine through activation of arginase-1, production of nitric oxide, and the up-regulation of reactive oxygen species (ROS).9 Arginase-1 inhibits

T-cell responses through depletion of nonessential amino acid, L-arginine, resulting in down-regulation of CD3-ζ and inhibition of T-cell proliferation.15, 16 Nitric oxide (NO) production in MDSCs is induced through up-regulation of inducible nitric oxide synthase (iNOS), NO down-regulates MHC class II in APCs and leads to T-cell apoptosis.17, 18 In leukocytes, ROS is primarily generated through NADPH oxidase. The oxidase is a multicomponent enzyme AZD5363 datasheet consisting of two membrane proteins, gp91 and p22, and at least four cytosolic components:

p47phox, p67phox, p40phox, and a small G protein Rac.19 In MDSCs a number of these components have been shown to be up-regulated, including p47phox and gp91.20 Notably, the regulation of these proteins was shown to be dependent on STAT3 activation, which provides further evidence for the importance of this transcription factor.20 Here we show that HCV induces the accumulation of MDSC through extracellular core protein. Human CD33+ cells cocultured with HCV-infected hepatocytes, or treated with HCV core,

suppress the activation of autologous T cells. Additionally, the suppression of T cells by HCV core-treated MDSCs is ROS-dependent. Core-treated CD33+ cells were CD14+CD11blow/+ and HLADR−/low. Further, HCV core treatment up-regulated NOX2 component, p47phox. Lastly, CD33+ cells from chronically infected patients were CD11b+CD14+ and HLADR−/low; these cells also up-regulated p47phox compared with healthy donors. These data provide evidence that HCV core induces the accumulation of ROS producing MDSCs, thereby inhibiting host T-cell responses. Therefore, this study describes a novel SPTLC1 mechanism for HCV-mediated immune regulation, and suggests that regulation of the MDSC population may be an attractive target for future HCV therapies. APC, antigen-presenting cell; DC, dendritic cell; IFN-α, interferon-alpha; IL, interleukin; HCV, chronic hepatitis C virus; MDSC, myeloid-derived suppressor cell; PBMC, peripheral blood mononuclear cell; PMN, polymorphonuclear; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; TLR, Toll-like receptor. The human hepatoma cell line Huh 7.5.