Soluble epoxide hydrolase inhibitor, TPPU, increases regulatory T cells pathway in an arthritis model

FASEB J. 2020 Jul;34(7):9074-9086. doi: 10.1096/fj.202000415R. Epub 2020 May 13.

Abstract

Epoxyeicosatrienoic acids (EET) and related epoxy fatty acids (EpFA) are endogenous anti-inflammatory compounds, which are converted by the soluble epoxide hydrolase (sEH) to dihydroxylethersatrienoic acids (DHETs) with lessened biological effects. Inhibition of sEH is used as a strategy to increase EET levels leading to lower inflammation. Rheumatoid arthritis is a chronic autoimmune disease that leads to destruction of joint tissues. This pathogenesis involves a complex interplay between the immune system, and environmental factors. Here, we investigate the effects of inhibiting sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) on a collagen-induced arthritis model. The treatment with TPPU ameliorates hyperalgesia, edema, and decreases the expression of important pro-inflammatory cytokines of Th1 and Th17 profiles, while increasing Treg cells. Considering the challenges to control RA, this study provides robust data supporting that inhibition of the sEH is a promising target to treat arthritis.

Keywords: TPPU; Th1; Th17; Treg; rheumatoid arthritis; soluble epoxide hydrolase.

Publication types

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

MeSH terms

  • Animals
  • Arthritis, Experimental / chemically induced
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / pathology
  • Collagen / toxicity
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Inflammation / etiology
  • Inflammation / pathology
  • Inflammation / prevention & control*
  • Male
  • Mice
  • Mice, Inbred DBA
  • Phenylurea Compounds / pharmacology*
  • Piperidines / pharmacology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea
  • Phenylurea Compounds
  • Piperidines
  • Collagen
  • Epoxide Hydrolases