Anti-inflammatory effects of N-acylethanolamines in rheumatoid arthritis synovial cells are mediated by TRPV1 and TRPA1 in a COX-2 dependent manner
Open accessAbstract
INTRODUCTION: The endocannabinoid system modulates function of immune cells and mesenchymal cells such as fibroblasts, which contribute to cartilage destruction in rheumatoid arthritis (RA). The aim of the study was to determine the influence of N-acylethanolamines anandamide (AEA), palmitoylethanolamine (PEA) and oleylethanolamine (OEA) on several features of arthritic inflammation in vitro (human material) and in vivo (a mouse model). METHODS: Immunofluorescence and western blotting were used to detect cannabinoid receptors and related enzymes. Cytokines and MMP-3 were measured by ELISA. Intracellular signaling proteins were detected by proteome profiling. Proliferation was quantified by CTB reagent. Adhesion was assessed by the xCELLigence system. After onset of collagen type II arthritis, mice were treated daily with the FAAH inhibitor JNJ1661010 (20 mg/kg) or vehicle. RESULTS: IL-6, IL-8 and MMP-3 (determined only in synovial fibroblasts (SFs)) were downregulated in primary synoviocytes and SFs of RA and OA after AEA, PEA and OEA treatment. In SFs, this was due to activation of TRPV1 and TRPA1 in a COX-2-dependent fashion. FAAH inhibition increased the efficacy of AEA in primary synoviocytes but not in SFs. The effects of OEA and PEA on SFs were diminished by FAAH inhibition. Adhesion to fibronectin was increased in a CB1-dependent manner by AEA in OASFs. Furthermore, elevation of endocannabinoids ameliorated collagen-induced arthritis in mice. CONCLUSIONS: N-acylethanolamines exert anti-inflammatory effects in SFs. A dual FAAH/COX-2 inhibitor, increasing N-acylethanolamine levels with concomitant TRP channel desensitization, might be a good candidate to inhibit the production of proinflammatory mediators of synovial cells and to reduce erosions.
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In fibroblast-like synoviocytes derived from patients with rheumatoid arthritis and osteoarthritis, synthetic cannabinoid receptor agonists (CP55,940, WIN55,212, or Ajulemic acid) or AEA attenuate TNF-α stimulated production of the proinflammatory cytokines IL-6 and IL-8, and matrix degrading enzymes matrix metalloproteinases-1, -3, and -9.
“In FLSs derived from patients with rheumatoid arthritis and osteoarthritis, synthetic cannabinoid receptor agonists (CP55,940, WIN55,212, or Ajulemic acid) or AEA (Lowin et al, 2015) attenuate TNF-α stimulated production of the proinflammatory cytokines IL-6 and IL-8, and matrix degrading enzymes matrix metalloproteinases-1, -3, and -9 (Johnson et al, 2007;Lowin et al, 2015Lowin et al, , 2016;;Sel”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Lowin et al, 2015
AEA's attenuation of IL-6 and IL-8 is blocked by the TRPA1 antagonist A967079, but not by CB1 or CB2 receptor antagonists.
“AEA's attenuation of IL-6 and IL-8 is blocked by the TRPA1 antagonist A967079, but not by CB 1 or CB 2 receptor antagonists (Lowin et al, 2015), indicating that cannabinoids modulate inflammation through multiple pathways.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Lowin et al, 2015
In rheumatoid arthritis fibroblast-like synoviocytes stimulated by TNFα, AEA attenuates the phosphorylation of p38 and ERK1/2, but not cJUN, indicating a decrease in mitogen-activated protein kinase activation.
“In rheumatoid arthritis FLSs stimulated by TNFα, AEA attenuates the phosphorylation of p38 and ERK1/2, but not cJUN, indicating a decrease in mitogen-activated protein kinase activation (Lowin et al, 2015).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Lowin et al, 2015
Chronic FAAH inhibition reduces CIA-induced paw swelling and joint destruction.
“Furthermore, chronic FAAH inhibition reduces CIA-induced paw swelling (Kinsey et al, 2011b;Lowin et al, 2015) and joint destruction (Kinsey et al, 2011b).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Lowin et al, 2015
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References 38 · Cited by 94
- Authors
- Lowin, T., Apitz, M., Anders, S., & Straub, R. H.
- Affiliations
- University Hospital Regensburg (DE)
- Corresponding author
- Lowin, Torsten
- Venue
- Arthritis Research & Therapy
- Published
- 2015-11-14
- Volume
- 17
- Issue
- 1
- Pages
- 321-321
- ISSN
- 1478-6354 (ISSN-L)
- PMC
- PMC4644337
- OpenAlex
- W2173428397
- Cited by
- 94
- References
- 38
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 10 · 2022: 12 · 2021: 13 · 2020: 8 · 2019: 12 · 2018: 11 · 2017: 9 · 2016: 4
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Arthritis Research & Therapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- University of Regensburg Publication Server (University of Regensburg)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- N-acylethanolamines, anandamide, rheumatoid arthritis, synovial fibroblasts, TRPV1, TRPA1, cyclooxygenase-2, endocannabinoid system, FAAH inhibition, collagen-induced arthritis, anti-inflammatory activity, MMP-3, interleukin-6, interleukin-8, cell adhesion, CB1 receptor, osteoarthritis
- MeSH terms
- TRPA1 Cation Channel, Aged, Animals, Anti-Inflammatory Agents, Arthritis, Rheumatoid, Cells, Cultured, Dose-Response Relationship, Drug, Ethanolamines, Female, Humans, Male, Mice, Inbred DBA, Middle Aged, Nerve Tissue Proteins, Synovial Membrane, Calcium Channels, Inflammation Mediators, Transient Receptor Potential Channels, TRPV Cation Channels, Mice, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors
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