Notch signaling suppresses CD14⁺ monocytes cells activity in patients with chronic hepatitis C

Hepatitis C virus (HCV) infection always leads to chronic hepatitis via dysregulation of host immunity. Notch signaling also modulates the response of monocytes/macrophages. Thus, we aimed to investigate the regulatory role of Notch signaling to CD14⁺ monocytes. Forty patients with chronic hepatitis C and twenty normal controls (NC) were enrolled. CD14⁺ monocytes and CD4⁺ T cells were purified from peripheral bloods. Notch receptors' mRNA expression in CD14⁺ monocytes was semi-quantified by real-time PCR. Cytokine production by CD14⁺ monocytes in response to γ-secretase inhibitor (GSI) was investigated by ELISA. GSI-induced CD14⁺ monocytes activity to HCV clearance in Huh7.5 cells and to CD4⁺ T cell differentiation was also assessed in direct and indirect contact co-culture system. Notch1 mRNA relative level was approximately 10-fold elevated in CD14⁺ monocytes from chronic hepatitis C patients when compared with NC. GSI stimulation resulted in enhanced cytokines production by CD14⁺ monocytes from chronic hepatitis C patients. GSI-stimulated CD14⁺ monocytes from chronic hepatitis C patients induced suppression of HCV RNA replication in both direct and indirect contact co-culture system of CD14⁺ monocytes and HCVcc-infected Huh7.5 cells, and this process was accompanied by elevation of interferon-γ production but not increased target cell death. Moreover, GSI stimulation also enhanced CD14⁺ monocytes-induced Th1 and Th17 cells activation, and this process required direct cell-to-cell contact. Effective antiviral therapy down-regulated Notch1 mRNA expression and promoted cytokine production by CD14⁺ monocytes from chronic hepatitis C. Current data revealed an important immunoregulatory property of Notch signaling to CD14⁺ monocytes in chronic HCV infection.