09% versus 1.21 ± 0.90%) (Fig. 6B,C). We also observed a higher percentage of IL-4-producing cells in addition to IL-17-producing cells, but not IL-10-producing cells (data not shown). In addition, NS3/5 treatment also resulted in a significant induction of IL-17 production, while they reduced the production of IFN-γ (Fig. 6D). Collectively, these data indicate that IL-17-producing CD4+ T cells are induced during HCV Selleckchem Selumetinib infection. We next examined the possibility that the direct action of TSLP on CD4+ T cells is involved the differentiation of Th17 cells. CD4+ T cells from PBMC of HCV-infected

patients were stimulated with NS3/NS5 in the presence or absence of TSLP for 3 days. Stimulation with TSLP or NS3/5 significantly enhanced IL-17 mRNA and protein compared to control cells cultured medium only (Fig. 6E,F,G). Moreover, differentiation of IL-17 cells was increased following combined stimulation of TSLP and NS3/5 compared to either TSLP or NS3/5 alone. These results clearly

indicate that TSLP is an important factor in the differentiation of IL-17-producing CD4+ T cells during HCV infection and might play a role in the development of chronic liver diseases. In this www.selleckchem.com/products/CAL-101.html report we demonstrate that HCV infection of hepatocytes induces NFκB-dependent TSLP gene expression and protein production. Furthermore, TSLP mRNA and protein was increased selectively in liver tissues from chronic HCV patients. Intriguingly, TSLP released from HCV-infected hepatocytes activates human monocyte-derived DCs and conditions DCs to support the polarization of CD4+ T cells toward Th17 cells. The blockade of TSLP action by neutralizing antibody suppresses differentiation of Th17 cells. These results suggest a novel mechanism to account for the infiltration of TH17 cells

in the liver as MCE likely a result of the role of TSLP in promoting Th17 differentiation. However, it remains unclear whether hepatic TSLP accounts for facilitating the recruitment of Th17 infiltration in the infected liver. These results also raise the intriguing possibility that the crosstalk between HCV-infected hepatocytes and local (liver and/or liver draining lymph node) DCs may be a pivotal mechanism both in a defective antiviral (Th1) CD4+ T-cell response and also in an enhanced expression of an injury-provoking (Th17) CD4+ T-cell response. To our knowledge, our findings represent the first report identifying hepatic-secreted TSLP as a regulator of Th17 differentiation. Although CD4+ T cells have been reported to be critical to the antiviral function of CD8+ T cells in chronic infection, failure of CD4+ T cell help is associated with the inability to clear HCV infection and CD4+ T-cell responses in chronically infected HCV patients leans toward Th2 deviation and T regulatory (Treg) cells.