Category: Autoimmune rheumatologic diseases
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 (RA). 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 TH17-related genes. Accordingly, SFN significantly inhibited the activation of untransformed human T-cells derived from healthy donors or RA patients, and specifically downregulated the expression of the TH17-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 the GSH replenishing antioxidant N-acetyl-cysteine (NAC).
Together, our study provides mechanistic insights into the mode of action of the natural substance sulforaphane. It specifically exerts TH17 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 TH17 related chronic inflammatory/autoimmune diseases such as rheumatoid arthritis.
Jie Liang– University Hospital Heidelberg
Beate Jahraus– University Hospital Heidelberg
Emre Balta– University Hospital Heidelberg
Jacqueline Ziegler– University Hospital Heidelberg
Katrin Hübner– University Hospital Heidelberg
Norbert Blank– University Hospital Heidelberg
Beate Niesler– University Hospital Heidelberg
Guido Wabnitz– University Hospital Heidelberg
Yvonne Samstag– Professor for Immunology, University Hospital Heidelberg