Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes

Toxicol Appl Pharmacol. 2012 Aug 1;262(3):217-22. doi: 10.1016/j.taap.2012.05.004. Epub 2012 May 19.

Abstract

Trivalent inorganic arsenic [As(III)] is an efficient anticancer agent used to treat patients suffering from acute promyelocytic leukemia. Recently, experimental studies have clearly demonstrated that this metalloid can also cure lymphoproliferative and/or pro-inflammatory syndromes in different murine models of chronic immune-mediated diseases. T helper (Th) 1 and Th17 lymphocytes play a central role in development of these diseases, in mice and humans, especially by secreting the potent pro-inflammatory cytokine interferon-γ and IL-17A, respectively. As(III) impairs basic functions of human T cells but its ability to modulate secretion of pro-inflammatory cytokines by differentiated Th lymphocytes is unknown. In the present study, we demonstrate that As(III), used at concentrations clinically achievable in plasma of patients, has no effect on the secretion of interferon-γ from Th1 cells but almost totally blocks the expression and the release of IL-17A from human Th17 lymphocytes co-stimulated for five days with anti-CD3 and anti-CD28 antibodies, in the presence of differentiating cytokines. In addition, As(III) specifically reduces mRNA levels of the retinoic-related orphan receptor (ROR)C gene which encodes RORγt, a key transcription factor controlling optimal IL-17 expression in fully differentiated Th17 cells. The metalloid also blocks initial expression of IL-17 gene induced by the co-stimulation, probably in part by impairing activation of the JNK/c-Jun pathway. In conclusion, our results demonstrate that As(III) represses expression of the major pro-inflammatory cytokine IL-17A produced by human Th17 lymphocytes, thus strengthening the idea that As(III) may be useful to treat inflammatory immune-mediated diseases in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arsenicals / pharmacology*
  • Blotting, Western
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Interferon-gamma / analysis
  • Interleukin-17 / analysis
  • Interleukin-17 / antagonists & inhibitors*
  • Interleukin-17 / biosynthesis
  • Interleukin-2 / analysis
  • Interleukin-22
  • Interleukins / analysis
  • Lymphocyte Activation / drug effects
  • Real-Time Polymerase Chain Reaction
  • Th17 Cells / chemistry
  • Th17 Cells / drug effects*
  • Th17 Cells / metabolism
  • Th17 Cells / physiology

Substances

  • Arsenicals
  • IL17A protein, human
  • Interleukin-17
  • Interleukin-2
  • Interleukins
  • Interferon-gamma
  • interleukin-21