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Role of cannabinoid receptor 2 in mediating interleukin-1β-induced inflammation in rheumatoid arthritis synovial fibroblasts

1, 2, 3

  1. Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA, USA.
  2. Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA, USA.
  3. Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA, and Division of Rheumatology, University of Washington School of Medicine, Seattle, WA, USA. salah.ahmed@wsu.edu

CER11830 Submission on line
Full Papers

Rheumatology Article

 

Abstract

OBJECTIVES:
Recent studies showed that the expression of cannabinoid receptor 2 (CB2), not CB1, is upregulated at both the mRNA and protein levels in rheumatoid arthritis synovial fibroblasts (RASFs), however, little is known about its endogenous role in pro-inflammatory cytokine signalling in RASFs. Our aim was to investigate the role of CB2 receptor in mediating IL-1β-induced inflammation in human RASFs.
METHODS:
Human RASFs were pretreated with CB2 selective agonist (JWH-133), followed by stimulation with interleukin-1β (IL-1β, 10 ng/mL). The role of CB2 in IL-1β signalling was examined using small interfering RNA (siRNA) or an overexpression plasmid specific for CB2.
RESULTS:
Pretreatment with JWH-133 did not reduce IL-1β-induced IL-6 and IL-8 production and amplified the cellular expression of cyclooxygenase-2 (COX-2) by >2-fold in human RASFs. Furthermore, the knockdown of CB2 using siRNA markedly inhibited IL-1β-induced IL-6, IL-8, ENA-78, and RANTES production by more than 50% and completely abrogated COX-2 expression in human RASFs. MMP-2 and MMP-9 activity was also reduced by 50% with CB2 knockdown. On the contrary, overexpression of CB2 in human RASFs further increased IL-1β-induced IL-6, IL-8, and RANTES by approximately 3-fold whereas ENA-78 expression increased by 1.5-fold. Immunoprecipitation analysis to study the protein-protein interactions revealed that JWH-133 coordinates CB2 association with TGFβ-activated kinase 1 (TAK1), a key signalling molecule, to increase IL-1β-induced nuclear translocation of transcription factors nuclear factor-κBp65 (NF-κBp65) and activation protein-1 (AP-1).
CONCLUSIONS:
Overall, our results indicate for the first time that CB2 mediates IL-1β-induced signalling pathways in RASFs and may serve as a potential target to manage pain and inflammation in RA.

PMID: 30943136 [PubMed]

Received: 18/10/2018 - Accepted : 18/02/2019 - In Press: 18/03/2019