elafin and Arthritis--Rheumatoid

Alarm antiproteases, i.e. secretory leukocyte protease inhibitor ad elafin, are key mediators in innate immune response and integrate innate and adaptive immunity systems. The aim of the study was to assess clinical significance of serum levels of alarm antiproteases, elafin and secretory leukocyte protease inhibitor (SLPI) in patients with systemic sclerosis (SSc). Twenty-eight patients with SSc, 25 patients with rheumatoid arthritis (RA) and 22 healthy controls were recruited. Serum elafin and SLPI levels were examined using enzyme-linked immunosorbent assay (ELISA). The patients with SSc had significantly increased serum levels of SLPI in comparison with the RA patients and the healthy controls (p<0.01), and the RA patients presented significantly higher serum levels of elafin in comparison with the controls (p=0.003). In the SSc subgroup serum SLPI level negatively correlated with diffusing capacity of the lung for carbon monoxide (DLCO) (r=-0.41, p=0.03) and total lung capacity (r=-0.42, p=0.03). Both alarm antiproteases, elafin and SLPI could be potentially implicated in the pathogenesis of SSc and SLPI may be considered a candidate for serum biomarker of lung involvement in SSc.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Biomarkers; Elafin; Female; Humans; Immunity, Innate; Male; Middle Aged; Protease Inhibitors; Scleroderma, Systemic; Secretory Leukocyte Peptidase Inhibitor; Young Adult

Recent studies indicate that the anti-malarial agent artemisinin and its derivatives may exert an anti-inflammatory effect. In this study, we explored the effect of artesunate, an artemisinin derivative, on tumour necrosis factor (TNF)-alpha-induced production of interleukins, IL-1beta, IL-6 and IL-8, in human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), and further investigated the signal mechanism by which this compound modulates those cytokines' production.. RA FLS obtained from patients with active RA were stimulated with TNF-alpha and incubated with artesunate, and IL-1beta, IL-6 and IL-8 production was measured by ELISA. DNA-binding activity and nuclear translocation of nuclear factor kappa B (NF-kappaB) were measured by a sensitive multi-well colourimetric assay and confocal fluorescence microscopy, respectively. Signal transduction proteins expression was measured by western blot.. Artesunate decreased the secretion of IL-1beta, IL-6 and IL-8 from TNF-alpha-stimulated RA FLS in a dose-dependent manner. Artesunate also prevented TNF-alpha-induced nuclear NF-kappaB translocation, DNA-binding activity and gene transcriptional activity, as well as phosphorylation and degradation of IkappaBalpha, but phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase were unaffected. The production of IL-1beta, IL-6 and IL-8 induced by TNF-alpha was decreased by pyrrolidine dithiocarbamate (PDTC), a chemical inhibitor of NF-kappaB. These observations suggest that artesunate inhibits production of IL-1beta, IL-6 and IL-8 through inhibition of NF-kappaB signalling pathway. We also showed that artesunate prevented Akt phosphorylation. TNF-alpha-induced production of IL-1beta, IL-6 and IL-8 was hampered by treatment with the phosphatidylinositol 3 (PI3) kinase inhibitor LY294002, suggesting that inhibition of Akt activation might inhibit IL-1beta, IL-6 and IL-8 production induced by TNF-alpha.. Our results indicate that artesunate exerts an anti-inflammatory effect in RA FLS and provide the evidence that artesunate may have therapeutic potential for RA.

Topics: Aged; Antimalarials; Artemisinins; Artesunate; Arthritis, Rheumatoid; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Elafin; Female; Fibroblasts; Genes, Reporter; Humans; Inflammation Mediators; Middle Aged; NF-kappa B; Sesquiterpenes; Signal Transduction; Synovial Membrane; Tumor Necrosis Factor-alpha