Protein S exacerbates alcoholic hepatitis by stimulating liver natural killer T cells

Chelakkot-Govindalayathil, Ayshwarya-Lakshmi; Mifuji-Moroka, Rumi; D’Alessandro-Gabazza, Corina N.; Toda, Masaaki; Matsuda, Yoshikazu; Gil-Bernabe, Paloma; Roeen, Ziauraman; Yasuma, Taro; Yano, Yutaka; Gabazza, Esteban C.; Iwasa, Motoh; Takei, Yoshiyuki

doi:10.1111/jth.12789

Cited by 15 publications

(30 citation statements)

References 49 publications

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“…It inhibits inflammation by decreasing leukocyte infiltration and the release of cytokines (e.g., interleukin-6, tumor necrosis factor-a [TNF-a]) and chemokines (MCP-1) by stimulating apoptotic cell clearance through macrophage-mediated phagocytosis or by blocking cell apoptosis through TAM receptors and the Akt/PKB pathway (9,(11)(12)(13). PS suppression of apoptosis may prevent autoimmune responses, but it may also be deleterious in some conditions, such as cancer or hepatitis (14,19). In agreement with its antiapoptotic property, we show that hPS protects pancreatic islet b-cells from apoptosis and attenuates STZ-induced diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…The plasmid was digested, purified, and microinjected into fertilized eggs from C57BL/6J mice, and TG founders were screened by Southern blotting. Most hPS TG organs express hPS, and its mean plasma concentration is 85 6 3 mg/mL (14). Wildtype (WT) littermates were used as controls.…”

Section: Experimental Animalsmentioning

confidence: 99%

“…Homozygous human PS (hPS) transgenic (TG) mice on a C57BL/6 background have been previously characterized (14). Briefly, the full-length hPS cDNA was cloned into a pCAG plasmid containing the CAG-promoter (cytomegalovirus enhancer + chicken + b-actin promoter) and rabbit b-globin polyadenylation sites.…”

Section: Experimental Animalsmentioning

confidence: 99%

“…Thrombinantithrombin complex (Cedarlane Laboratories, Burlington, Ontario, Canada) and total plasminogen activator inhibitor-1 (PAI-1) (E1/PAI-1; R&D Systems, Minneapolis, MN) were measured with enzyme immunosorbent assay (EIA) kits and total collagen and hydroxyproline as previously described (15). Complement C4BP was assayed with an EIA kit from Assaypro (St. Charles, MO) and total hPS as previously described (14). To assess free hPS, a 96-well microplate was coated with C4BP (ATGen Corp., Sampyeong-dong, Korea), and after appropriate washing and blocking, biotin-labeled polyclonal rabbit anti-hPS antibody (DakoCytomation, Glostrup, Denmark) was added.…”

Section: Biochemical Analysismentioning

confidence: 99%

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Amelioration of Diabetes by Protein S

et al. 2016

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Protein S is an anticoagulant factor that also regulates inflammation and cell apoptosis. The effect of protein S on diabetes and its complications is unknown. This study compared the development of diabetes between wildtype and transgenic mice overexpressing human protein S and the development of diabetic glomerulosclerosis between mice treated with and without human protein S and between wild-type and protein S transgenic mice. Mice overexpressing protein S showed significant improvements in blood glucose level, glucose tolerance, insulin sensitivity, and insulin secretion compared with wild-type counterparts. Exogenous protein S improved insulin sensitivity in adipocytes, skeletal muscle, and liver cell lines in db/db mice compared with controls. Significant inhibition of apoptosis with increased expression of BIRC3 and Bcl-2 and enhanced activation of Akt/PKB was induced by protein S in islet b-cells compared with controls. Diabetic wild-type mice treated with protein S and diabetic protein S transgenic mice developed significantly less severe diabetic glomerulosclerosis than controls. Patients with type 2 diabetes had significantly lower circulating free protein S than healthy control subjects. This study shows that protein S attenuates diabetes by inhibiting apoptosis of b-cells and the development of diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Section: Experimental Animalsmentioning

confidence: 99%

Section: Experimental Animalsmentioning

confidence: 99%

Section: Biochemical Analysismentioning

confidence: 99%

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Amelioration of Diabetes by Protein S

et al. 2016

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“…hPS‐TG mice backcrossed to C57BL/6J mice for > 10 generations were previously characterized, and wild‐type (WT) littermates were used as controls . Similar biological activity of both murine PS and hPS and binding of hPS to murine TAM receptors have been previously reported . The WT mice treated with exogenous hPS were purchased from Nihon SLC (Hamamatsu, Japan).…”

Section: Methodsmentioning

confidence: 99%

Protein S is protective in pulmonary fibrosis

Urawa

Kobayashi

D’Alessandro-Gabazza

et al. 2016

Journal of Thrombosis and Haemostasis

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Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin‐induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin‐induced pulmonary fibrosis. Summary BackgroundPulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. ObjectivesTo evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and ResultsThe circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild‐type mice, and exogenous protein S or vehicle was administered to wild‐type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S‐transgenic mice as compared with wild‐type mice. Wild‐type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase‐3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild‐type counterparts. Protein S also inhibited apoptosis of alveolar epithelial cells in vitro. ConclusionsThese observations suggest clinical relevance and a protective role of protein S in pulmonary fibrosis.

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