Sulforaphane Inhibits Inflammatory Responses of Primary Human T-Cells by Increasing ROS and Depleting Glutathione

Front Immunol. 2018 Nov 14;9:2584. doi: 10.3389/fimmu.2018.02584. eCollection 2018.

Abstract

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 TH17-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 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 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 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.

Keywords: TH17; glutathione; primary human T-cells; reactive oxygen species; rheumatoid arthritis; sulforaphane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents / pharmacology*
  • Arthritis, Rheumatoid / drug therapy*
  • Brassicaceae / immunology
  • Cells, Cultured
  • Down-Regulation
  • Glutathione / metabolism
  • Humans
  • Immunosuppression
  • Inflammation / drug therapy*
  • Interleukin-17 / metabolism
  • Interleukins / metabolism
  • Isothiocyanates / pharmacology*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Primary Cell Culture
  • Reactive Oxygen Species / metabolism
  • STAT3 Transcription Factor / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*

Substances

  • Anti-Inflammatory Agents
  • Interleukin-17
  • Interleukins
  • Isothiocyanates
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Reactive Oxygen Species
  • STAT3 Transcription Factor
  • sulforaphane
  • Glutathione
  • interleukin-22