Dissertation

Evaluation of The Endocannabinoid System in Rheumatoid Arthritis

Fechtner, Sabrina Catherine

2019

Overview

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by activated synovial fibroblasts in which pro-inflammatory cytokine interleukin-1β (IL-1β) mediates inflammation. The endocannabinoid system (ECS) is comprised of two evolutionarily conserved cannabinoid receptors 1 and 2 (CB1 and CB2) which elicit their effects through Gαi/o mediated signaling. Recent studies show that CB2 expression is upregulated in rheumatoid arthritis synovial fibroblasts (RASFs) as compared to normal synovial fibroblasts. However, the role of the ECS in inflammation remains poorly understood. Here, we characterized the role of CB2 activation in IL-1β-induced inflammation in RASFs. Using JWH-133 an agonist highly specific to CB2, we found that direct activation of CB2 does not reduce IL-1β-induced inflammation. To our surprise, we observed CB2 expression contributes to IL-1β induced inflammation in RASFs. We found that JWH-015, an agonist for CB2 with less specificity than JWH-133, inhibits IL-1β induced inflammation in RASFs, suggesting the involvement of another receptor in producing anti-inflammatory effects. In a rat adjuvant-induced arthritis (AIA) model of human RA, JWH-015 elicited anti-inflammatory, antinociceptive, and bone protective effects. Further molecular docking studies using JWH-015 as a ligand showed that JWH-015 utilizes the glucocorticoid receptor (GR) for its anti-inflammatory properties. In the final stages of my studies, we characterized the role of IL-1α in RASFs. We found IL-1α is upregulated selectively by IL-1β; and due to its localization in the nucleus, IL-1α is able to self-stabilize its expression and IL-1β’s expression by interacting with transcription factor NF-κBp65. In addition to these studies, we also investigated the molecular mechanisms of anti-inflammatory properties of green tea catechins in RASFs. Although epigallocatechin gallate is the most effective catechin at inhibiting downstream inflammatory signaling, we found that its effectiveness may be reduced in the presence of epicatechin (EC). Therefore, varying EC content in green tea may reduce the anti-inflammatory effects of other potential catechins. These studies altogether provide evidence for the following applications:(1) targeting CB2 as a therapy for RA, (2) using agonists like JWH-015 as therapies for pain management in RA, (3) targeting IL-1α to ameliorate IL-1β in RA, and (4) the general therapeutic properties of compounds in green tea.

• Publisher: ProQuest Dissertations & Theses
• Subject: Biology / Molecular biology / Pharmaceutical sciences / Physiology / Public health
• ISBN: 1085563979, 9781085563970