11β-Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis

Int Immunopharmacol. 2013 Nov;17(3):489-94. doi: 10.1016/j.intimp.2013.07.015. Epub 2013 Aug 11.

Abstract

11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) plays an important role in inflammation. However, the role of 11β-HSD1 in rheumatoid arthritis (RA) remains unknown. The purpose of this study was to evaluate the therapeutic effects of a selective 11β-HSD1 inhibitor BVT-2733 in collagen-induced arthritis (CIA) and its underlying mechanisms. CIA mice were treated with BVT-2733 (100 mg/kg, orally) or vehicle twice daily for 2 weeks. Arthritis score and joint histology were investigated. The levels of pro-inflammatory cytokines as well as anti-type II collagen antibody (anti-CII) were detected by ELISA. Western blot analysis was used to assess the activation of NF-κB and NLRP1 inflammasome in joint tissues and in human RA synovial cells. BVT-2733 treatment attenuated the arthritis severity and anti-CII level in CIA mice. BVT-2733 also decreased the levels of serum TNF-α, IL-1β, IL-6 and IL-17. BVT-2733 treatment also significantly reduced synovial inflammation and joint destruction. NF-κB activation and NLRP1 inflammasome assembly were also inhibited in arthritic joints and human RA synovial cells. In conclusion, BVT-2733 exhibits an anti-inflammatory effect on CIA. This protective effect is, at least partly, mediated by inhibition of the NF-κB and NLRP1 inflammasome signaling pathways. 11β-HSD1 inhibition may represent a potential therapeutic target for RA patients.

Keywords: 11β-Hydroxysteroid dehydrogenase 1; BVT-2733; NF-κB; NLRP1 inflammasome; Rheumatoid arthritis.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / metabolism
  • Arthritis, Experimental / diagnostic imaging
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / metabolism
  • Arthritis, Experimental / pathology
  • Arthritis, Rheumatoid
  • Cells, Cultured
  • Cytokines / blood
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Foot Joints / diagnostic imaging
  • Foot Joints / metabolism
  • Foot Joints / pathology
  • Humans
  • Immunoglobulin G / blood
  • Male
  • Mice
  • Mice, Inbred DBA
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Piperazines / pharmacology
  • Piperazines / therapeutic use*
  • Radiography
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use*
  • Synovial Membrane / cytology
  • Thiazoles / pharmacology
  • Thiazoles / therapeutic use*

Substances

  • 3-chloro-2-methyl-N-(4-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-1,3-thiazol-2-yl)benzenesulfonamide
  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Cytokines
  • Enzyme Inhibitors
  • Immunoglobulin G
  • NALP1 protein, mouse
  • NF-kappa B
  • Piperazines
  • Sulfonamides
  • Thiazoles
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1