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

Abstract

Z. Notch signaling suppresses CD14 + monocytes cells activity in patients with chronic hepatitis C, APMIS 2019; 127: 642-652.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 csecretase 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-c 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.

Increased Interleukin-35 suppresses peripheral CD14+ monocytes function in patients with Kawasaki disease

“…CD14 + monocytes are important components of innate immune response, and take part in the immunopathogenesis of autoimmune disorders, cancers, and infectious diseases. As the indirect antigen presenting cells and co-stimulatory signaling transducer, CD14 + monocytes induced the activation and differentiation of CD4 + T cells in rheumatoid arthritis [31], lung squamous carcinoma [32], and chronic hepatitis C [33]. In consistent with these previous reports, we found that CD14 + monocytes from patients with Kawasaki disease only effectively promoted the activation and differentiation of naïve CD4 + T cells into IFN-γ-producing Th1 and IL-17A-producing Th17 cells under direct contact condition.…”

“…In consistent with these previous reports, we found that CD14 + monocytes from patients with Kawasaki disease only effectively promoted the activation and differentiation of naïve CD4 + T cells into IFN-γ-producing Th1 and IL-17A-producing Th17 cells under direct contact condition. Furthermore, various factors, including CD147 [31], IL-7 [32], and Notching signaling pathway [33], could directly regulate the differential activity of CD14 + monocytes. IL-35 also dampened CD14 + monocytes-induced naïve CD4 + T cells activation in Kawasaki disease, indicating that elevated IL-35 might play a protective role to suppress extensive adaptive immune response in Kawasaki disease.…”

“…The low-level control was defined as the LDH level in HUVECs cultured alone, while the high-level control was defined as the LDH level in Triton X-100 treated HUVECs. The frequency of target cell death was calculated using the following equation: (experiment valuelow-level control)/(high-level controllowlevel control) × 100% [33].…”

Increased Interleukin-35 Suppresses Peripheral CD14+ Monocytes Function in Patients with Kawasaki Disease

“…The low-level control was defined as the LDH level in HUVECs cultured alone, while the high-level control was defined as the LDH level in Triton X-100 treated HUVECs. The frequency of target cell death was calculated using the following equation: (experiment value -low-level control)/(high-level control -low-level control) × 100% [21].…”

“…CD14 + monocytes are important components of innate immune response, and take part in the immunopathogenesis of autoimmune disorders, cancers, and infectious diseases. As the indirect antigen presenting cells and co-stimulatory signaling transducer, CD14 + monocytes induced the activation and differentiation of CD4 + T cells in rheumatoid arthritis [32], lung squamous carcinoma[33], and chronic hepatitis C[21]. In consistent with these previous reports, we found that CD14 + monocytes from patients with Kawasaki disease only effectively promoted the activation and differentiation of naïve CD4 + T cells into IFN-γ-producing Th1 and IL-17A-producingTh17 cells under direct contact condition.…”