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Impact of glucocorticoids on systemic sirtuin 1 expression and activity in rats with adjuvant-induced arthritis.

ABSTRACT: The class III histone deacetylase sirtuin 1 (SIRT1) plays a pivotal role in numerous biological and physiological functions, including inflammation. An association between SIRT1 and proinflammatory cytokines might exist. In addition to their important role in inflammation associated with rheumatoid arthritis (RA), proinflammatory cytokines mediate the development of systemic effects. Here, we evaluated systemic SIRT1 expression and enzymatic activity, in peripheral blood mononuclear cells (PBMCs) and in liver isolated from rats with adjuvant-induced arthritis (AIA), treated or not with low or high doses of glucocorticoids (GCs). We also measured the production of tumour necrosis factor alpha (TNF) and interleukin-1 beta (IL-1 beta) in PBMCs and liver. We found that SIRT1 expression and activity increased in PBMCs of AIA rats compared to healthy controls and decreased under GC treatment. Similarly, we observed an increased SIRT1 activity in the liver of AIA rats compared to healthy controls which decreased under high doses of GCs. We also found an increase in IL-1 beta and TNF levels in the liver of AIA rats compared to healthy controls, which decreased under high doses of GC. We did not observe a significant correlation between SIRT1 activity and proinflammatory cytokine production in PBMC or liver. In contrast, a strong positive correlation was found between the liver levels of TNF and IL-1 beta (rho=0.9503, p=7.5x10^-21). Our results indicate that increased inflammation in AIA rats compared to healthy control is accompanied by an increased SIRT1 activity in both PBMCs and liver, which could be decreased under GC treatment.

SUBMITTER: Pasquereau S

PROVIDER: S-EPMC7889198 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, which occurs in ~1.0% of the general population. Increasing studies have suggested that long non?coding RNAs (lncRNAs) may serve important roles in various biological processes and may be associated with the pathogenesis of different types of disease, including RA. Astragalosides (AST) has been used as a traditional Chinese medicine for the treatment of RA. However, the mechanism underlying its therapeutic effect has remained unclear to date. Thus, there is an urgent need to elucidate the possible mechanism of AST in the treatment of RA from the perspective of lncRNAs. In the present study, the lncRNAs and mRNAs of a vehicle group, animal model group and AST treatment (control) group were determined by Arraystar Rat lncRNA/mRNA microarray. The differentially expressed genes with a fold change >1.5 and P<0.05 were selected and analyzed. Gene Ontology (GO) and pathway analysis was performed using the Database for Annotation, Visualization and Integration Discovery, and the coding?non?coding gene co?expression network was drawn based on the correlation analysis between the differentially expressed lncRNAs and mRNAs. Based on node degree and the correlation between bioinformatics analysis and RA, the critical differentially expressed lncRNAs were selected, analyzed and verified by reverse transcription?quantitative PCR (RT?qPCR) analysis. The results showed that, following AST treatment, up to 75 lncRNAs and 247 mRNAs were found to be differentially expressed among the three groups. GO and pathway analysis manifested that 135 GO terms and 17 pathways were enriched by differentially expressed genes. Four lncRNAs (MRAK012530, MRAK132628, MRAK003448 and XR_006457) were selected as the critical lncRNAs and their trend in expression showed consistency between the RT?qPCR and microarray data. In conclusion, AST had a regulatory effect on differentially expressed lncRNAs during the development of RA, and four lncRNAs could be selected as critical therapeutic targets of AST.

Project description:[(11)C] PBR28 binding to translocator protein (TSPO) was evaluated for imaging of acute and chronic inflammation using two established rat models.Acute inflammation was induced by local carrageenan injection into the paw of Fisher 344 rats (model A). T-cell mediated adjuvant arthritis was induced by heat-inactivated Mycobacterium butyricum injection in Lewis rats (model B). Micro-PET scan was performed after injection of approximately 35 MBq [(11)C]PBR28. In model A, volumes of interest (VOIs) were defined in the paw of Fisher 344 rats (n=6) with contralateral sham treatment as control. For model B, VOIs were defined in the tail, sacroiliac joints, hips, knees and thigh muscles of M. butyricum treated animals (n=8) and compared with sham-treated controls (n=4). The peak (11)C-PBR28 SUV (SUVpeak) and area under the curve (AUCSUV) of 60-minute time-activity data were calculated. Immunohistochemistry for CD68, a macrophage stain, was performed from paw tissues. In addition, the [(11)C]PBR28 cell uptake was measured in lipopolysaccharide (LPS)-stimulated and non-stimulated macrophage cultures.LPS-stimulated macrophages displayed dose-dependent increased [(11)C]PBR28 uptake, which was blocked by non-labeled PBR28. In both models, radiotracer uptake of treated lesions increased rapidly within minutes and displayed overall accumulative kinetics. The SUVpeak and AUCSUV of carrageenan-treated paws was significantly increased compared to controls. Also, the [(11)C]PBR28 uptake ratio of carrageenan-treated vs. sham-treated paw correlated significantly with CD68 staining ratios of the same animals. In adjuvant arthritis, significantly increased [(11)C]PBR28 SUVpeak and AUCSUV values were identified at the tail, knees, and sacroiliac joints, while no significant differences were identified in the lumbar spine and hips.Based on our initial data, [(11)C]PBR28 PET appears to have potential for imaging of various inflammatory processes involving macrophage activation.

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Impact of glucocorticoids on systemic sirtuin 1 expression and activity in rats with adjuvant-induced arthritis.

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