| Autor: |
Liang J; Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany., Jahraus B; Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany., Balta E; Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany., Ziegler JD; Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany., Hübner K; Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany., Blank N; Division of Rheumatology, Department of Internal Medicine V, Heidelberg University, Heidelberg, Germany., Niesler B; Department of Human Molecular Genetics, Heidelberg University, Heidelberg, Germany.; nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University, Heidelberg, Germany., Wabnitz GH; Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany., Samstag Y; Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany. |
| Abstrakt: |
The activity and function of T-cells are influenced by the intra- and extracellular redox milieu. Oxidative stress induces hypo responsiveness of untransformed T-cells. Vice versa increased glutathione (GSH) levels or decreased levels of reactive oxygen species (ROS) prime T-cell metabolism for inflammation, e.g., in rheumatoid arthritis. Therefore, balancing the T-cell redox milieu may represent a promising new option for therapeutic immune modulation. Here we show that sulforaphane (SFN), a compound derived from plants of the Brassicaceae family, e.g., broccoli, induces a pro-oxidative state in untransformed human T-cells of healthy donors or RA patients. This manifested as an increase of intracellular ROS and a marked decrease of GSH. Consistently, increased global cysteine sulfenylation was detected. Importantly, a major target for SFN-mediated protein oxidation was STAT3, a transcription factor involved in the regulation of T H 17-related genes. Accordingly, SFN significantly inhibited the activation of untransformed human T-cells derived from healthy donors or RA patients, and downregulated the expression of the transcription factor RORγt, and the T H 17-related cytokines IL-17A, IL-17F, and IL-22, which play a major role within the pathophysiology of many chronic inflammatory/autoimmune diseases. The inhibitory effects of SFN could be abolished by exogenously supplied GSH and by the GSH replenishing antioxidant N-acetylcysteine (NAC). Together, our study provides mechanistic insights into the mode of action of the natural substance SFN. It specifically exerts T H 17 prone immunosuppressive effects on untransformed human T-cells by decreasing GSH and accumulation of ROS. Thus, SFN may offer novel clinical options for the treatment of T H 17 related chronic inflammatory/autoimmune diseases such as rheumatoid arthritis. |
