concanavalin-a and ebselen

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 micro M 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 micro M 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.

Topics: Allergens; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigen Presentation; Azoles; Clone Cells; Concanavalin A; Dendritic Cells; Dermatitis, Contact; Epitopes, T-Lymphocyte; Female; Irritants; Isoindoles; Lipopolysaccharides; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Transgenic; Organoselenium Compounds; Oxazolone; Reactive Oxygen Species; Th1 Cells

The seleno-organic drug ebselen (2-phenyl-1, 2-benzoisoselenazol-3(2H)-one) has glutathione peroxidase-like activity, and inhibits lipoxygenases, oxidative burst of leukocytes, nitric oxide synthases, protein kinases and leukocyte migration. This study elaborates in vivo in mice hitherto unknown immunopharmacological properties of ebselen. The compound was comparatively investigated in two different T cell-dependent hepatic hyperinflammation models and in two alternative models of receptor-activated liver apoptosis. Mice orally pretreated with ebselen were dose-dependently protected from concanavalin A (ConA)-induced liver injury. In livers from ebselen-pretreated mice exposed to ConA, the nuclear antiapoptotic transcription factor NFkappaB was upregulated. The release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF) was downregulated, while the ciculating amount of the anti-inflammatory cytokine interleukin-10 (IL-10) was increased. Ebselen protected also from liver injury induced by the superantigen staphylococcal enterotoxin B in galactosamine (GalN)-sensitized mice. Furthermore, ebselen protected the liver and enhanced circulating IL-10 in GalN-sensitized mice treated with recombinant TNF, i.e., the common distal mediator of ConA and SEB-induced hepatotoxicity. The activation of apoptosis-executing proteases, i.e., caspases, was blocked in livers of ebselen-treated mice following TNF receptor, but not following CD95 receptor activation. We propose a novel mechanism for the immunomodulatory properties of the drug and suggest that it might be useful in the therapy of T cell-mediated inflammatory disorders.

Topics: Animals; Apoptosis; Azoles; Caspases; Concanavalin A; Enterotoxins; Enzyme Activation; Immunosuppressive Agents; Isoindoles; Liver; Liver Failure; Mice; Mice, Inbred BALB C; NF-kappa B; Organoselenium Compounds; T-Lymphocytes; Tumor Necrosis Factor-alpha