Defective response to Toll‐like receptor 3 and 4 ligands by activated monocytes in chronic hepatitis C virus infection

Abstract

Toll-like receptors (TLR) have a critical role in innate immunity against pathogens. We investigated the cytokine response to TLR stimulation in peripheral blood cells of subjects infected with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) in the Women Interagency HIV Study (WIHS) cohort. Interleukin (IL)-6 in response to TLR3 and TLR4 ligands such as polyinosinic-polycytidylic acid and lipopolysaccharide was significantly compromised in HCV-infected women. High spontaneous secretion of IL-6 suggested pre-existing cell activation as a factor mediating reduced responses to TLR3 and TLR4 stimulation. To a lesser extent, tumour necrosis factor-alpha and IL-1beta responses to TLR stimulation were also compromised. Monocytes, but not B cells or NK cells, were identified as the cell population spontaneously secreting cytokines and also as the cells responding to TLR stimulation. These results highlight a functional defect in antigen-presenting cells of women with HCV infection or co-infection. In women with existing HIV co-infection, decreased cytokine function of antigen-presenting cells suggests another mechanism contributing to immune dysfunction in addition to the HIV-associated CD4 defect.

Hepatitis C Virus Core Protein Induces Homotolerance and Cross‐Tolerance to Toll‐Like Receptor Ligands by Activation of Toll‐Like Receptor 2

“…Impaired production of IL-6 by monocytes from HCV-infected patients is associated with reduced production of IL-17 by allogeneic T cells in the presence of TLR ligands. These results are supported by those of Villacres et al [28], who report a reduced IL-6 response to TLR ligands by PBMCs isolated from patients with HCV infection. They found that IL-6 production by PBMCs from patients with HCV in- fection was significantly decreased after stimulation with TLR4 ligands [28].…”

“…These results are supported by those of Villacres et al [28], who report a reduced IL-6 response to TLR ligands by PBMCs isolated from patients with HCV infection. They found that IL-6 production by PBMCs from patients with HCV in- fection was significantly decreased after stimulation with TLR4 ligands [28]. In addition, another report shows that DCs isolated from HCV-infected patients exhibit an impaired production of TNF-a in response to TLR4 ligands [29].…”

Macrophages in Hepatitis B and Hepatitis C Virus Infections

“…Similarly, via interactions with gC1qR (a surface complement receptor), the HCV core protein inhibits TLR4-induced production of IL-12 by macrophages (94). Peripheral blood monocytes taken from HCV-infected patients preferentially express IL-10 upon exposure to recombinant HCV, which may contribute to reduced T-cell responses (96) and exhibit defective responses to TLR3 and TLR4 ligands (92). It is currently not clear whether these cells are functionally impaired by the virus or whether they have adapted an altered and reversible phenotype due to external stimuli (plasticity).…”

Brief Report: CD14brightCD16− monocytes and sCD14 level negatively associate with CD4-memory T-cell frequency and predict HCV-decline on therapy

“…Circulating monocytes are also capable of infiltrating into the liver and serving as precursors to Kuppfer cells [36]. Upon stimulation, classical-monocytes shed CD14 [11], CD163, and produce IP-10, IL-6 and TNF [12, 14]. Here sCD14 negatively associated with CEF-specific IFNγ-response (Fig.…”