Pyrrolidine dithiocarbamate (PDTC) inhibits inflammatory signaling via expression of regulator of calcineurin activity 1 (RCAN1): Anti-inflammatory mechanism of PDTC through RCAN1 induction

Biochem Pharmacol. 2017 Nov 1:143:107-117. doi: 10.1016/j.bcp.2017.07.011. Epub 2017 Jul 14.

Abstract

Pyrrolidine dithiocarbamate (PDTC) is a thiol compound that elicits anti-inflammatory effects by inhibiting NF-κB signaling. In this study, we report that regulator of calcineurin activity 1 (RCAN1) expression is induced by PDTC treatment and that increased RCAN1 expression is dependent on the generation of reactive oxygen species (ROS) and activation of p38 MAPK and JNK signaling. We also report that the ability of PDTC to induce RCAN1 is mediated by activator protein-1 (AP-1)-dependent gene transcription, and identified a functional AP-1 binding site in the RCAN1 promoter by producing mutations and conducting chromatin immunoprecipitation (ChIP) analyses. Moreover, we show that the PDTC-mediated inhibitory effect on NF-κB signaling is significantly perturbed by knocking out RCAN1. Our data provide the first evidence that PDTC prevents in vivo expression of pro-inflammatory cytokines by inducing RCAN1 expression.

Keywords: Calcineurin; Inflammation; PDTC; RCAN1.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Calcium-Binding Proteins
  • Chromatin Immunoprecipitation
  • Cytokines / blood
  • Cytokines / immunology
  • Cytokines / metabolism*
  • DNA-Binding Proteins
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / biosynthesis*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Muscle Proteins / biosynthesis*
  • Muscle Proteins / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • Pyrrolidines / pharmacology*
  • Signal Transduction
  • Thiocarbamates / pharmacology*
  • Transcription, Genetic

Substances

  • Antioxidants
  • Calcium-Binding Proteins
  • Cytokines
  • DNA-Binding Proteins
  • DSCR1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • NF-kappa B
  • Pyrrolidines
  • RCAN1 protein, human
  • Thiocarbamates
  • pyrrolidine dithiocarbamic acid