Article
The ghrelin system is regulated by nutrient availability and pro-inflammatory cytokines in rheumatoid arthritis synovial fibroblasts
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Published: | October 8, 2019 |
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Background: Ghrelin is an orexigenic neuropeptide and its levels are decreased in patients with rheumatoid arthritis. Ghrelin downregulates pro-inflammatory cytokine production in T cells and monocytes and could therefore be beneficial to treat chronic inflammatory diseases. Synovial fibroblasts are one major contributor of joint destruction and cytokine production in the rheumatoid joint but the influence of the ghrelinergic system on fibroblast function has not been investigated yet.
Methods: Components of the ghrelin system were detected using cell-based ELISA, western blotting and immunofluorescent staining. Cytokine and MMP production were assessed by ELISA.
Results: We detected all components of the ghrelin system including ghrelin, the activating enzyme ghrelin-O-acyltransferase (GOAT), and its receptor growth hormone secretagogue (GHR-S) in synovial tissue and isolated synovial fibroblasts. GOAT was found to be regulated by TNF and glucose, whereas ghrelin was increased by IFN-γ (+48%, p=0.01) and TNF (+23%, p=0.03). GHR-S was not regulated on individual fibroblasts but was expressed throughout synovial tissue. The biased agonist YIL-781 at GHR-S downregulated TNF-induced IL-6 by 44% (p<0.001), IL-8 by 18 % (p<0.001) and MMP3 production by 44% (p<0.001).
Conclusion: Our findings strengthen the view of the ghrelin system as an anti-inflammatory response to counteract excessive cytokine production. Its mechanism of action might include regulation of glucose uptake and consequently nutrient supply which is necessary to cope with energy needs during cell activation.