Generation and Function of Reactive Oxygen Species in Dendritic Cells During Antigen Presentation

Abstract

Although reactive oxygen species (ROS) have long been considered to play pathogenic roles in various disorders, this classic view is now being challenged by the recent discovery of their physiological roles in cellular signaling. To determine the immunological consequence of pharmacological disruption of endogenous redox regulation, we used a selenium-containing antioxidant compound ebselen known to modulate both thioredoxin and glutaredoxin pathways. Ebselen at 5–20 μM inhibited Con A-induced proliferation and cytokine production by the HDK-1 T cell line as well as the LPS-triggered cytokine production by XS52 dendritic cell (DC) line. Working with the in vitro-reconstituted Ag presentation system composed of bone marrow-derived DC, CD4+ T cells purified from DO11.10 TCR-transgenic mice and OVA peptide (serving as Ag), we observed that 1) both T cells and DC elevate intracellular oxidation states upon Ag-specific interaction; 2) ebselen significantly inhibits ROS production in both populations; and 3) ebselen at 5–20 μM inhibits DC-induced proliferation and cytokine production by T cells as well as T cell-induced cytokine production by DC. Thus, Ag-specific, bidirectional DC-T cell communication can be blocked by interfering with the redox regulation pathways. Allergic contact hypersensitivity responses in BALB/c mice to oxazolone, but not irritant contact hypersensitivity responses to croton oil, were suppressed significantly by postchallenge treatment with oral administrations of ebselen (100 mg/kg per day). These results provide both conceptual and technical frameworks for studying ROS-dependent regulation of DC-T cell communication during Ag presentation and for testing the potential utility of antioxidants for the treatment of immunological disease.

Effect of lipopolysaccharide, skin sensitizers and irritants on thioredoxin-1 expression in dendritic cells: relevance of different signalling pathways

“…It was also demonstrated that the redox imbalance induced by skin sensitizers is important in the regulation of DC functions [5,38,39,41,47,61]. Therefore, the increase in Trx-1 mRNA expression observed in .…”

“…LPS is recognised by a LPS-activation cluster [56] that could activate two diVerent pathways. Upon stimulation with LPS, ROS production occurs [39,62], which appears to break the inactive complex reduced Trx-1/ASK1, thus allowing the subsequent recruitment of TRAF6 to the ASK1 signalosome [21,54]. The activated ASK1 signalosome induces Nrf2/ ARE-mediated expression [66], which is involved in Trx-1 protein expression [29,67].…”

Toll Receptor-Mediated Regulation of NADPH Oxidase in Human Dendritic Cells

“…In DC, oxygen radicals were implicated in both DC differentiation (43) and maturation (26,27) and in IL-8/CXCL8 production (24,25). Controversial data are present in the literature about the inhibitory action (52) or the positive role (26,53) of oxygen radicals on the ability of DC to stimulate T cell response. To evaluate the contribution of NADPH oxidase-dependent oxygen radicals on DC functions, we generated DC from monocytes obtained from CGD patients.…”

Genetics of Autoimmune Diseases: A Multistep Process

“…ROS response has been reported not only in phagocytes but also in antigen-presenting cells (APCs), such as dendritic cells (DCs) [30]. Also, T cells have been reported to express Ncf1 during antigen presentation and activation [31], adding further complexity to the process of finding the mechanisms behind the phenotype.…”

“…There are a number of pathways that are proposed to be affected by free radicals and state of oxidation. On the antigenpresenting level, it has been shown that by inhibiting ROS production, the proliferation of T cells in response to antigen presentation of DCs is prevented [30], suggesting that the burst response in an APC could modulate the antigen presentation capacity of that cell.…”