Abstract:Objective. Results of studies in mice suggest a protective role for TRAIL in arthritis. The aim of this study was to investigate the role of TRAIL in patients with rheumatoid arthritis (RA).Methods. In the present study, we compared RA fibroblast-like synoviocytes (FLS) that were resistant or sensitive to TRAIL-induced apoptosis and the expression of TRAIL receptors in these cells, and also investigated the clinical features of the patients from whom the FLS were derived. Furthermore, we evaluated the levels o… Show more
“…sTRAIL is detectable in the serum/plasma of healthy individuals [82–84], and is increased in patients with autoimmune diseases (such as systemic sclerosis, systemic lupus erythematosus (SLE), rheumatoid arthritis) [82,85,86] and viral infection such as human immunodeficiency virus (HIV) [87]. In contrast, serum/plasma concentrations of sTRAIL are decreased in patients with ischemic heart disease [88,89].…”
Objective
Pregnancy is characterized by activation of the innate immune response demonstrated by phenotypic and metabolic changes in granulocytes and monocytes. This state of activation has been implicated in the pathophysiology of multiorgan dysfunction of pregnant women with acute viral or bacterial infection. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the mediators responsible for neutrophil apoptosis. Gene deletion of TRAIL results in delayed neutrophil apoptosis and resolution of inflammation after the administration of bacterial endotoxin. The aim of this study was to determine if maternal plasma concentrations of the soluble form of TRAIL (sTRAIL) differ in women with uncomplicated pregnancy and those with acute pyelonephritis.
Method
A cross-sectional study was conducted to include women in the following groups: 1) non-pregnant (n=23); 2) uncomplicated pregnancies (n=93); and 3) pregnancies with acute pyelonephritis (n=23). Plasma concentrations of sTRAIL were determined by ELISA.
Results
1) Women with uncomplicated pregnancies had a lower mean plasma sTRAIL concentration (pg/mL) than non-pregnant women (31.5 ± 10.1 vs. 53.3 ± 12.5; p < 0.001); 2) plasma sTRAIL concentrations did not change as a function of gestational age (Pearson correlation = −0.1; p=0.4); 3) the mean plasma sTRAIL concentration (pg/mL) was significantly lower in pregnant women with acute pyelonephritis than in those with uncomplicated pregnancies (20.5 ± 6.6 vs. 31.5 ± 10.1; p<0.001); and 4) among patients with acute pyelonephritis, patients with bacteremia had a significantly lower mean plasma concentration of sTRAIL (pg/mL) than those without bacteremia (15.1 ± 4.8 vs. 24.7 ± 4.6; p< 0.001).
Conclusion
Women with uncomplicated pregnancies are associated with a significantly lower mean maternal plasma concentration of sTRAIL than that observed in non-pregnant women. Moreover, a further decrease of plasma sTRAIL concentration was observed in pregnant women with acute pyelonephritis, and this could account, at least in part, for the exaggerated intravascular inflammatory response previously reported in pyelonephritis during pregnancy.
“…sTRAIL is detectable in the serum/plasma of healthy individuals [82–84], and is increased in patients with autoimmune diseases (such as systemic sclerosis, systemic lupus erythematosus (SLE), rheumatoid arthritis) [82,85,86] and viral infection such as human immunodeficiency virus (HIV) [87]. In contrast, serum/plasma concentrations of sTRAIL are decreased in patients with ischemic heart disease [88,89].…”
Objective
Pregnancy is characterized by activation of the innate immune response demonstrated by phenotypic and metabolic changes in granulocytes and monocytes. This state of activation has been implicated in the pathophysiology of multiorgan dysfunction of pregnant women with acute viral or bacterial infection. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the mediators responsible for neutrophil apoptosis. Gene deletion of TRAIL results in delayed neutrophil apoptosis and resolution of inflammation after the administration of bacterial endotoxin. The aim of this study was to determine if maternal plasma concentrations of the soluble form of TRAIL (sTRAIL) differ in women with uncomplicated pregnancy and those with acute pyelonephritis.
Method
A cross-sectional study was conducted to include women in the following groups: 1) non-pregnant (n=23); 2) uncomplicated pregnancies (n=93); and 3) pregnancies with acute pyelonephritis (n=23). Plasma concentrations of sTRAIL were determined by ELISA.
Results
1) Women with uncomplicated pregnancies had a lower mean plasma sTRAIL concentration (pg/mL) than non-pregnant women (31.5 ± 10.1 vs. 53.3 ± 12.5; p < 0.001); 2) plasma sTRAIL concentrations did not change as a function of gestational age (Pearson correlation = −0.1; p=0.4); 3) the mean plasma sTRAIL concentration (pg/mL) was significantly lower in pregnant women with acute pyelonephritis than in those with uncomplicated pregnancies (20.5 ± 6.6 vs. 31.5 ± 10.1; p<0.001); and 4) among patients with acute pyelonephritis, patients with bacteremia had a significantly lower mean plasma concentration of sTRAIL (pg/mL) than those without bacteremia (15.1 ± 4.8 vs. 24.7 ± 4.6; p< 0.001).
Conclusion
Women with uncomplicated pregnancies are associated with a significantly lower mean maternal plasma concentration of sTRAIL than that observed in non-pregnant women. Moreover, a further decrease of plasma sTRAIL concentration was observed in pregnant women with acute pyelonephritis, and this could account, at least in part, for the exaggerated intravascular inflammatory response previously reported in pyelonephritis during pregnancy.
“…47 Anomalies in pathways that promote invasiveness and cytokine secretion also favour survival of RA FLS by increasing expression of antiapoptotic molecules, such as apoptosis regulator Bcl-2 (which is over expressed in synovial samples from patients with RA 12 ), and by decreasing or altering the response to ligation of apoptosis-regulating receptors, such as TNF receptor superfamily (TNFRSF) member 6 (also known as CD95 and FAS) 13,48 and TNFRSF10A (also known as TRAIL receptor 1). 49 Reduced apoptosis can, in part, be secondary to increased expression and engagement of integrins on FLS in the RA synovium. 47 Intrinsic deficiencies in apoptosis-specific pathways are also reportedly prominent in RA FLS, especially abnormalities in the p53 pathway.…”
Section: Molecular Pathology Of Fls In Ramentioning
Rheumatoid arthritis (RA) is characterized by hyperplastic synovial pannus tissue, which mediates destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS) are a key component of this invasive synovium and have a major role in the initiation and perpetuation of destructive joint inflammation. The pathogenic potential of FLS in RA stems from their ability to express immunomodulating cytokines and mediators as well as a wide array of adhesion molecule and matrix-modelling enzymes. FLS can be viewed as ‘passive responders’ to the immunoreactive process in RA, their activated phenotype reflecting the proinflammatory milieu. However, FLS from patients with RA also display unique aggressive features that are autonomous and vertically transmitted, and these cells can behave as primary promoters of inflammation. The molecular bases of this ‘imprinted aggressor’ phenotype are being clarified through genetic and epigenetic studies. The dual behaviour of FLS in RA suggests that FLS-directed therapies could become a complementary approach to immune-directed therapies in this disease. Pathophysiological characteristics of FLS in RA, as well as progress in targeting these cells, are reviewed in this manuscript.
“…TRAIL, another receptor for OPG, has been found to promote the apoptosis of chondrocytes in vitro (Pettersen et al 2002). According to research by Audo et al (2011), TRAIL only plays a protective role in the early phase of RA (possibly the first 6 months) and has a deleterious role later on. A possible explanation might lie in its pro-apoptosis effects on chondrocytes.…”
Our aim is to elucidate the effects of osteoproteogerin (OPG) on cartilage destruction in rats as a model of collagen-induced arthritis (CIA). To establish the CIA model, Sprague Dawley rats were injected with bovine type II collagen solution subcutaneously via the tails. Adenovirus-mediated OPG (Ad-OPG) was then injected intra-articularly either at the beginning of CIA (early OPG treatment) or one week after CIA establishment (late OPG treatment); vehicle or Ad-green fluorescent protein were injected as controls. The rats were killed 4 weeks after treatment. Ankle-joint sections were obtained for histology. Serum samples were collected for enzyme-linked immunosorbent assay. Safranin O staining showed that proteoglycan loss was inhibited in the early and late Ad-OPG groups. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining revealed that both early and late Ad-OPG treatments significantly prevented chondrocyte apoptosis in CIA rats. Furthermore, disintegrin and metalloproteinase with thrombospondin motif-5 expression decreased remarkably in the early and late OPG treatment groups. However, the cartilage destruction score, cartilage oligomeric matrix protein level and caspase-3 expression were only decreased in the early Ad-OPG treatment group. Additionally, ankle-joint swelling and the interleukin-1β expression level in CIA rats were not notably altered by Ad-OPG treatment. Taken together, our results suggest that early Ad-OPG treatment has potent protective effects against cartilage destruction during rheumatoid arthritis progression, mainly by reducing proteoglycan loss and chondrocyte apoptosis.
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