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Anti-inflammatory effects of N-acylethanolamines in rheumatoid arthritis synovial cells are mediated by TRPV1 and TRPA1 in a COX-2 dependent manner.

Lowin T, Apitz M, Anders S, Straub RH - Arthritis Res. Ther. (2015)

Bottom Line: The effects of OEA and PEA on SFs were diminished by FAAH inhibition.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Franz Josef Strauss Allee 11, 93042, Regensburg, Germany. torsten.lowin@ukr.de.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Impact of anandamide on mitogen-activated protein kinase pathways in RASF. a-f Analysis of p38α phosphorylation (a, b), ERK1/2 phosphorylation (c, d) and cJun phosphorylation (e, f) under TNF treatment with or without AEA pretreatment under normoxic (a, c, e) and hypoxic (b, d, f) conditions. Paired t test was used for comparisons. Number of patients included was n = 4 (a, c, e) and n = 5 (b, d, f). AEA anandamide, RA rheumatoid arthritis, SF synovial fibroblast(s), TNF tumor necrosis factor
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Fig6: Impact of anandamide on mitogen-activated protein kinase pathways in RASF. a-f Analysis of p38α phosphorylation (a, b), ERK1/2 phosphorylation (c, d) and cJun phosphorylation (e, f) under TNF treatment with or without AEA pretreatment under normoxic (a, c, e) and hypoxic (b, d, f) conditions. Paired t test was used for comparisons. Number of patients included was n = 4 (a, c, e) and n = 5 (b, d, f). AEA anandamide, RA rheumatoid arthritis, SF synovial fibroblast(s), TNF tumor necrosis factor

Mentions: To address the question how EC modulate proinflammatory cytokine signaling, proteome profiling was employed to detect changes in phosphorylation of proinflammatory intracellular signaling proteins. Preincubation of SF with AEA 5 h prior to TNF (10 ng/ml) treatment significantly reduced phosphorylation of p38α (Fig. 6a) and ERK1/2 (Fig. 6c) but not cJUN (Fig. 6e) in RASF. This only occurred under hypoxic but not normoxic conditions (Fig. 6b, d).Fig. 6


Anti-inflammatory effects of N-acylethanolamines in rheumatoid arthritis synovial cells are mediated by TRPV1 and TRPA1 in a COX-2 dependent manner.

Lowin T, Apitz M, Anders S, Straub RH - Arthritis Res. Ther. (2015)

Impact of anandamide on mitogen-activated protein kinase pathways in RASF. a-f Analysis of p38α phosphorylation (a, b), ERK1/2 phosphorylation (c, d) and cJun phosphorylation (e, f) under TNF treatment with or without AEA pretreatment under normoxic (a, c, e) and hypoxic (b, d, f) conditions. Paired t test was used for comparisons. Number of patients included was n = 4 (a, c, e) and n = 5 (b, d, f). AEA anandamide, RA rheumatoid arthritis, SF synovial fibroblast(s), TNF tumor necrosis factor
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4644337&req=5

Fig6: Impact of anandamide on mitogen-activated protein kinase pathways in RASF. a-f Analysis of p38α phosphorylation (a, b), ERK1/2 phosphorylation (c, d) and cJun phosphorylation (e, f) under TNF treatment with or without AEA pretreatment under normoxic (a, c, e) and hypoxic (b, d, f) conditions. Paired t test was used for comparisons. Number of patients included was n = 4 (a, c, e) and n = 5 (b, d, f). AEA anandamide, RA rheumatoid arthritis, SF synovial fibroblast(s), TNF tumor necrosis factor
Mentions: To address the question how EC modulate proinflammatory cytokine signaling, proteome profiling was employed to detect changes in phosphorylation of proinflammatory intracellular signaling proteins. Preincubation of SF with AEA 5 h prior to TNF (10 ng/ml) treatment significantly reduced phosphorylation of p38α (Fig. 6a) and ERK1/2 (Fig. 6c) but not cJUN (Fig. 6e) in RASF. This only occurred under hypoxic but not normoxic conditions (Fig. 6b, d).Fig. 6

Bottom Line: The effects of OEA and PEA on SFs were diminished by FAAH inhibition.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Franz Josef Strauss Allee 11, 93042, Regensburg, Germany. torsten.lowin@ukr.de.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus