HEMA-induced oxidative stress inhibits NF-κB nuclear translocation and TNF release from LTA- and LPS-stimulated immunocompetent cells

Objective: The release of inflammatory cytokines from antigen-stimulated cells of the Resin monomer immune system is inhibited by resin monomers such as 2-hydroxyethyl methacrylate HEMA (HEMA). Although the formation of oxidative stress in cells exposed to HEMA is firmly estab- Oxidative stress lished, the mechanism behind the inhibited cytokine secretion is only partly known. The Cytokine present investigation presents evidence regarding the role of HEMA-induced oxidative stress NF-KB in the secretion of the pro-inflammatory cytokine TNFoL from cells exposed to the antigens Nrf2 LTA (lipoteichoic acid) or LPS (lipopolysaccharide) of cariogenic microorganisms using BSO (L-buthionine sulfoximine) or NAC (N-acetyl cysteine) to inhibit or stabilize the amounts of the antioxidant glutathione. Method: RAW264.7 mouse macrophages were treated with LTA, LPS or HEMA in the presence of BSO or NAC for 1h or 24h. Secretion of TNFoL from cell cultures was analyzed by ELISA, and the formation of reactive oxygen (ROS) or nitrogen species (RNS) was determined by flow cytometry. Protein expression was detected by Western blotting. Results: The release of TNF alpha in both LTA- and LPS-exposed cells was decreased by HEMA, and this concentration-dependent inhibitory effect was amplified by BSO or NAC. LTA- and LPS-stimulated expression of the redox-sensitive transcription factor NF-alpha B (p65) in cell nuclei decreased in the presence of HEMA because the translocation of p65 from the cytosol was prevented by oxidative stress specifically increased by the monomer. Conclusions: A disturbance of the cellular redox balance, particularly induced by HEMA, is a crucial factor in the inhibition of LTA- and LPS-stimulated signalling pathways leading to TNF alpha secretion. (C) 2020 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved

Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity

Broad T cell and B cell responses to multiple HCV antigens are observed early in individuals who control or clear HCV infection. The prevailing hypothesis has been that similar immune responses induced by prophylactic immunization would reduce acute virus replication and protect exposed individuals from chronic infection. Here, we demonstrate that immunization of naïve chimpanzees with a multicomponent HCV vaccine induced robust HCV-specific immune responses, and that all vaccinees exposed to heterologous chimpanzee-adapted HCV 1b J4 significantly reduced viral RNA in serum by 84%, and in liver by 99% as compared to controls (P=0.024 and 0.028, respectively). However, despite control of HCV in plasma and liver in the acute period, in the chronic phase, 3 of 4 vaccinated animals developed persistent infection. Analysis of expression levels of proinflammatory cytokines in serial hepatic biopsies failed to reveal an association with vaccine outcome. However, expression of IDO, CTLA-4 [corrected] and PD-1 levels in liver correlated with clearance or chronicity.Despite early control of virus load, a virus-associated tolerogenic-like state can develop in certain individuals independent of vaccination history

Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity

Broad T cell and B cell responses to multiple HCV antigens are observed early in individuals who control or clear HCV infection. The prevailing hypothesis has been that similar immune responses induced by prophylactic immunization would reduce acute virus replication and protect exposed individuals from chronic infection. Here, we demonstrate that immunization of naïve chimpanzees with a multicomponent HCV vaccine induced robust HCV-specific immune responses, and that all vaccinees exposed to heterologous chimpanzee-adapted HCV 1b J4 significantly reduced viral RNA in serum by 84%, and in liver by 99% as compared to controls (P=0.024 and 0.028, respectively). However, despite control of HCV in plasma and liver in the acute period, in the chronic phase, 3 of 4 vaccinated animals developed persistent infection. Analysis of expression levels of proinflammatory cytokines in serial hepatic biopsies failed to reveal an association with vaccine outcome. However, expression of IDO, CTLA-4 [corrected] and PD-1 levels in liver correlated with clearance or chronicity. CONCLUSION: Despite early control of virus load, a virus-associated tolerogenic-like state can develop in certain individuals independent of vaccination history