Thrombomodulin inhibits the activation of eosinophils and mast cells

Roeen, Ziaurahman; Toda, Masaaki; D’Alessandro-Gabazza, Corina N.; Onishi, Masahiro; Kobayashi, Tetsu; Yasuma, Taro; Urawa, Masahito; Taguchi, Osamu; Gabazza, Esteban C.

doi:10.1016/j.cellimm.2014.11.005

Cited by 10 publications

(7 citation statements)

References 20 publications

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“…13 The TMthrombin complex increases the generation of activated protein C (APC), an anticoagulant with anti-inflammatory and cytoprotective activity, by activating protein C. In addition, TM alone can directly downregulate the inflammatory response by inhibiting the activity of high-mobility group protein B-1 (HMGB1), by suppressing immunogenic dendritic cells, eosinophils, mast cells, and the complement system. [13][14][15][16][17][18] There are published results showing preventive effects of TM in diabetic renopathy and ischemia-reperfusion renal injury. [19][20][21] However, no study has assessed the effect of recombinant TM on progressive kidney fibrosis induced by TGFb1, a common driver of renal fibrosis in several diseases causing CKD.…”

Section: Translational Statementmentioning

confidence: 99%

Thrombomodulin ameliorates transforming growth factor-β1–mediated chronic kidney disease via the G-protein coupled receptor 15/Akt signal pathway

Takeshita

Yasuma

Nishihama

et al. 2020

Kidney International

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Kidney fibrosis is the common consequence of chronic kidney diseases that inexorably progresses to end-stage kidney disease with organ failure treatable only with replacement therapy. Since transforming growth factor-b1 is the main player in the pathogenesis of kidney fibrosis, we posed the hypothesis that recombinant thrombomodulin can ameliorate transforming growth factor-b1-mediated progressive kidney fibrosis and failure. To interrogate our hypothesis, we generated a novel glomerulus-specific human transforming growth factor-b1 transgenic mouse to evaluate the therapeutic effect of recombinant thrombomodulin. This transgenic mouse developed progressive glomerular sclerosis and tubulointerstitial fibrosis with kidney failure. Therapy with recombinant thrombomodulin for four weeks significantly inhibited kidney fibrosis and improved organ function compared to untreated transgenic mice. Treatment with recombinant thrombomodulin significantly inhibited apoptosis and mesenchymal differentiation of podocytes by interacting with the G-protein coupled receptor 15 to activate the Akt signaling pathway and to upregulate the expression of anti-apoptotic proteins including survivin. Thus, our study strongly suggests the potential therapeutic efficacy of recombinant thrombomodulin for the treatment of chronic kidney disease and subsequent organ failure.

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Section: Translational Statementmentioning

confidence: 99%

Thrombomodulin ameliorates transforming growth factor-β1–mediated chronic kidney disease via the G-protein coupled receptor 15/Akt signal pathway

Takeshita

Yasuma

Nishihama

et al. 2020

Kidney International

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“…Previous studies have shown that rhTM modulates excessive immune responses by inhibiting the activation of several immune cells, including dendritic cells, eosinophils, and T cells [ 13 , 14 , 16 ]. To assess the effect of rhTM on the systemic immune response in our present STZ-induced DM mouse model, we compared the percentage of spleen immune cells between diabetic mice treated with rhTM or SAL.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, besides inhibiting apoptosis, the beneficial effects of thrombomodulin administration in our DM model may also be attributed to its anti-inflammatory and immunomodulatory activity. Previous studies have shown that rhTM inhibits the activation of eosinophils and mast cells and enhances dendritic cells’ tolerogenic activity as well as the proportion of regulatory T cells in lymphoid tissue [ 14 , 16 , 45 ]. In agreement with these studies, we found here that diabetic mice treated with rhTM had an increased proportion of regulatory CD4+/CD25+ T cells and tolerogenic plasmacytoid dendritic cells in the spleen compared to control mice.…”

Section: Discussionmentioning

confidence: 99%

“…After binding to TM, thrombin loses its procoagulant property to promote anticoagulant activity by converting the anticoagulant protein C to its active form activated protein C (APC) [ 13 ]. Apart from its anticoagulant activity, TM also inhibits inflammation and the immune response by blocking the high-mobility group protein B-1 (HMGB1), by suppressing the activity of immune cells and the activation of the complement system, and by inhibiting cell apoptosis via its G-protein-coupled receptor 15 [ 13 , 14 , 16 , 17 ]. TM also promotes antioxidant activity by enhancing the nuclear factor (erythroid-derived 2)-like 2 (NRF2) nuclear translocation antioxidant pathway [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus

Okano

Takeshita

Yasuma

et al. 2021

Cells

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Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic β-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional β-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit β-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of β-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic β-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet β-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.

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“…22 Besides its prominent role in inflammation, Epx was shown to contribute to airway obstruction in asthma patients by mediating mucus plug formation. 23 In cluster B, we detected thrombomodulin (Thbd), which is an important cell adhesion-factor 24 and was shown to inhibit degranulation of EOS 25 and pathophysiological processes in asthma via modulation of dendritic cell immunostimulatory properties. Due its immune modulatory properties, Thbd has also been proposed as a drug candidate for asthma prevention.…”

Section: Discussionmentioning

confidence: 99%