Cannabinoid Receptor 2 Agonist JWH-015 Inhibits Interleukin-1β-Induced Inflammation in Rheumatoid Arthritis Synovial Fibroblasts and in Adjuvant Induced Arthritis Rat via Glucocorticoid Receptor.

Sabrina Fechtner,Salahuddin Ahmed,Ila Srivastava,Tim R Muench,Anil K Singh,Christopher T Szlenk,Senthil Natesan

doi:10.3389/fimmu.2019.01027

Abstract

Management of pain in the treatment of rheumatoid arthritis (RA) is a priority that is not fully addressed by the conventional therapies. In the present study, we evaluated the efficacy of cannabinoid receptor 2 (CB2) agonist JWH-015 using RA synovial fibroblasts (RASFs) obtained from patients diagnosed with RA and in a rat adjuvant-induced arthritis (AIA) model of RA. Pretreatment of human RASFs with JWH-015 (10–20 μM) markedly inhibited the ability of pro-inflammatory cytokine interleukin-1β (IL-1β) to induce production of IL-6 and IL-8 and cellular expression of inflammatory cyclooxygenase-2 (COX-2). JWH-015 was effective in reducing IL-1β-induced phosphorylation of TAK1 (Thr184/187) and JNK/SAPK in human RASFs. While the knockdown of CB2 in RASFs using siRNA method reduced IL-1β-induced inflammation, JWH-015 was still effective in eliciting its anti-inflammatory effects despite the absence of CB2, suggesting the role of non-canonical or an off-target receptor. Computational studies using molecular docking and molecular dynamics simulations showed that JWH-105 favorably binds to glucocorticoid receptor (GR) with the binding pose and interactions similar to its well-known ligand dexamethasone. Furthermore, knockdown of GR using siRNA abrogated JWH-015's ability to reduce IL-1β-induced IL-6 and IL-8 production. In vivo, administration of JWH-015 (5 mg/kg, daily i.p. for 7 days at the onset of arthritis) significantly ameliorated AIA in rats. Pain assessment studies using von Frey method showed a marked antinociception in AIA rats treated with JWH-015. In addition, JWH-015 treatment inhibited bone destruction as evident from micro-CT scanning and bone analysis on the harvested joints and modulated serum RANKL and OPG levels. Overall, our findings suggest that CB2 agonist JWH-015 elicits anti-inflammatory effects partly through GR. This compound could further be tested as an adjunct therapy for the management of pain and tissue destruction as a non-opioid for RA.

Highlights

In 1990, cannabinoid receptor 1 (CB1) was identified as the receptor responsible for tetrahydrocannabinol carboxylic (THC) effects [1]
The findings from the present study provide an evidence for the anti-inflammatory role of a cannabinoid receptor 2 (CB2) agonist JWH-015 in regulating IL-1β activated inflammatory responses in human RA synovial fibroblasts (RASFs) and a rat Adjuvant-Induced Arthritis (AIA) model of human Rheumatoid arthritis (RA)
We have identified how JWH-015 does not utilize CB2 for its anti-inflammatory actions, rather we demonstrated that JWH015 has the capability of interacting with the glucocorticoid receptor (GR) receptor

Summary

Introduction

In 1990, cannabinoid receptor 1 (CB1) was identified as the receptor responsible for tetrahydrocannabinol carboxylic (THC) effects [1]. CB2 is mainly expressed peripherally, with its highest expression on immune cells. It is thereby associated with the immune suppressive and anti-inflammatory effect of cannabinoids [2, 3]. Since the discovery of these receptors, endogenous ligands of the ECS such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) have been identified, and their synthesis and metabolism have been characterized. In addition to the endogenous ligands, several exogenous ligands have been identified such as cannabidiol (CBD). These ligands activate the ECS, they lack specificity to one receptor or the other. As our understanding of the ECS grows, specific ligands of either CB1 or CB2 are needed to characterize each receptor separately

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Results

Conclusion