bay-11-7082 and Autoimmune-Diseases

Systemic autoimmune diseases can damage nearly every tissue or cell type of the body. Although a great deal of progress has been made in understanding the pathogenesis of autoimmune diseases, current therapies have not been improved, remain unspecific and are associated with significant side effects. Because dendritic cells (DCs) play a major role in promoting immune tolerance against self-antigens (self-Ags), current efforts are focusing at generating new therapies based on the transfer of tolerogenic DCs (tolDCs) during autoimmunity. However, the feasibility of this approach during systemic autoimmunity has yet to be evaluated. TolDCs may ameliorate autoimmunity mainly by restoring T cell tolerance and, thus, indirectly modulating autoantibody development. In vitro induction of tolDCs loaded with immunodominant self-Ags and subsequent cell transfer to patients would be a specific new therapy that will avoid systemic immunosuppression. Herein, we review recent approaches evaluating the potential of tolDCs for the treatment of systemic autoimmune disorders.

Topics: Anti-Inflammatory Agents; Autoimmune Diseases; B-Lymphocytes; Cholecalciferol; Dendritic Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immune Tolerance; Nitriles; Sulfones; T-Lymphocytes

Topics: Animals; Autoimmune Diseases; Dendritic Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; I-kappa B Kinase; Interferon Type I; Interferon-alpha; Lupus Erythematosus, Systemic; Mevalonic Acid; Mice; Molecular Targeted Therapy; NF-kappa B; Nitriles; Rats; rho GTP-Binding Proteins; Sulfones

The fungal secondary metabolite panepoxydone has been recently described as an inhibitor of NF-kappaB activation which is a pivotal regulator of the inflammatory and immune response. These findings have led to propose that panepoxydone may be useful as anti-inflammatory agent. In this study we investigated for the first time the effects of panepoxydone on inflammatory gene expression in the monocytic cell line MonoMac6, stimulated with lipopolysaccharide (LPS) and the phorbolester 12-O-tetradecanoylphorbol-13-acetate (TPA). DNA microarray analysis of 110 human genes known to be strongly regulated during inflammation, combined with reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) revealed that low micromolar concentrations (12-24 microM) of panepoxydone strongly inhibited the expression of thirty-three NF-kappaB dependent pro-inflammatory genes such as the chemokines CCL3, CCL4, CCL8; CXCL8, CXCL10, CXCL20, the cytokines IL-1, IL-6, TNF-alpha, pro-inflammatory enzymes like COX-2, and components of the REL/NF-kappaB/IkappaB family without significant effects on the expression of house-keeping genes. Panepoxydone strongly inhibited hTNF-alpha, IL-8 and NF-kappaB promoter activity in LPS/TPA stimulated MonoMac6 cells with IC(50) values of 0.5-1 microg/ml by blocking the phosphorylation of IkappaB and subsequent binding of the activated NF-kappaB transcription factor to the DNA. From our data, panepoxydone may serve as lead structure for the development of transcription-based inhibitors of pro-inflammatory gene expression.

Topics: Apoptosis; Autoimmune Diseases; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Survival; Electrophoretic Mobility Shift Assay; Fluorescein-5-isothiocyanate; Gene Expression; Genes, Reporter; Humans; Inflammation; Lipopolysaccharides; NF-kappa B; Nitriles; Oligonucleotide Array Sequence Analysis; Propidium; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfones; Tetradecanoylphorbol Acetate