Trichloroethylene Alters Th1/Th2/Th17/Treg Paradigm in Mice: A Novel Mechanism for Chemically Induced Autoimmunity

Int J Toxicol. Mar/Apr 2018;37(2):155-163. doi: 10.1177/1091581818757036. Epub 2018 Mar 19.

Abstract

The role of environmental factors in autoimmune diseases has been increasingly recognized. While major advance has been made in understanding biological pathogen-induced autoimmune diseases, chemically triggered autoimmunity is poorly understood. Trichloroethylene (TCE), a common environmental pollutant, has recently been shown to induce autoimmunity. This study explored whether TCE could cause imbalance of T helper (Th) cell subsets which would contribute to the pathogenesis of TCE-induced medicamentosa-like dermatitis. BALB/c mice were treated with TCE via drinking water at doses of 2.5 or 5.0 mg/mL for 2, 4, 8, 12, and 16 weeks. Trichloroethylene exposure caused time- and dose-dependent increase in Th1, Th2, and Th17 and decrease in regulatory cell (Treg) in the spleen at 2, 4, 8, 12, and 16 weeks, with greatest changes mainly at 4 weeks. These effects were mirrored by similar changes in the expression of their corresponding cytokines interferon-γ, interleukin 4 (IL-4), IL-17A, and IL-10. Mechanistically, these phenotypic changes were accounted for by alterations to their respective master transcription factors T-box expressed in T cells, GATA-binding protein 3, Retinoic acid-related orphan receptor ct (RORct), and forkhead box P3. Of interest, TCE treatment shifted the ratios of Th1/Th2 and Th17/Treg; specifically, TCE increased Th17/Treg. These findings provide the first evidence that TCE exposure significantly changes the Th1/Th2/Th17/Treg paradigm and their specific cytokines driven by altered master transcription factors. This may promote autoimmune reactions in the pathogenesis of TCE-induced skin sensitization and associated damage to other tissues.

Keywords: IFN-γ; IL-10; IL-17A; IL-4; Th1/Th2/Th17/Treg paradigm; trichloroethylene.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / drug effects*
  • Cytokines / immunology
  • Female
  • Mice, Inbred BALB C
  • Solvents / toxicity*
  • Spleen / cytology
  • Spleen / drug effects
  • Spleen / immunology
  • T-Lymphocytes, Helper-Inducer / drug effects*
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • Trichloroethylene / toxicity*

Substances

  • Cytokines
  • Solvents
  • Trichloroethylene