BACKGROUND: Hepatitis C virus (HCV) activates host innate immune responses mediated by retinoic acid inducing gene-I (RIG-I) and Toll-like receptors (TLRs). Although the nonstructural protein 3/4A (NS3/4A) of HCV disrupts interferon responses by inhibiting RIG-I signaling, the effects of TLR activation by HCV-associated proteins on host innate immune responses are poorly understood. METHODS: Proinflammatory cytokine responses to various TLR ligands in human antigen-presenting cells (APCs) were examined either with or without prestimulation by HCV core protein. RESULTS: TLR2 activation by the HCV core protein leads to a decrease in interleukin 6 (IL-6) production by human APCs after subsequent stimulation with TLR2 (homotolerance) ligands and TLR4 (cross-tolerance) ligands. This hyporesponsiveness induced by preexposure to the HCV core protein was partially mediated by the negative regulation of nuclear factor-kappaB activation by the induction of IRAK-M. TLR ligand-induced IL-6 production was significantly reduced in peripheral blood monocytes isolated from HCV-infected patients, compared with those of healthy control subjects. Alloantigen presentation by monocytes isolated from HCV-infected patients results in impaired production of interleukin 17 by naive CD4(+) T cells in the presence of TLR ligands. CONCLUSIONS: Chronic stimulation of APCs with HCV core protein is associated with hyporesponsiveness in TLR-mediated innate immunity.
BACKGROUND:Hepatitis C virus (HCV) activates host innate immune responses mediated by retinoic acid inducing gene-I (RIG-I) and Toll-like receptors (TLRs). Although the nonstructural protein 3/4A (NS3/4A) of HCV disrupts interferon responses by inhibiting RIG-I signaling, the effects of TLR activation by HCV-associated proteins on host innate immune responses are poorly understood. METHODS: Proinflammatory cytokine responses to various TLR ligands in human antigen-presenting cells (APCs) were examined either with or without prestimulation by HCV core protein. RESULTS:TLR2 activation by the HCV core protein leads to a decrease in interleukin 6 (IL-6) production by human APCs after subsequent stimulation with TLR2 (homotolerance) ligands and TLR4 (cross-tolerance) ligands. This hyporesponsiveness induced by preexposure to the HCV core protein was partially mediated by the negative regulation of nuclear factor-kappaB activation by the induction of IRAK-M. TLR ligand-induced IL-6 production was significantly reduced in peripheral blood monocytes isolated from HCV-infectedpatients, compared with those of healthy control subjects. Alloantigen presentation by monocytes isolated from HCV-infectedpatients results in impaired production of interleukin 17 by naive CD4(+) T cells in the presence of TLR ligands. CONCLUSIONS: Chronic stimulation of APCs with HCV core protein is associated with hyporesponsiveness in TLR-mediated innate immunity.
Authors: Qun Wu; Linda F van Dyk; Di Jiang; Azzeddine Dakhama; Liwu Li; Steven R White; Ashley Gross; Hong Wei Chu Journal: Virology Date: 2013-08-30 Impact factor: 3.616
Authors: María Martínez-Esparza; María Tristán-Manzano; Antonio J Ruiz-Alcaraz; Pilar García-Peñarrubia Journal: World J Gastroenterol Date: 2015-11-07 Impact factor: 5.742