| 1. |
- Hasan, Zirak, et al.
(author)
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Rho-kinase regulates induction of T-cell immune dysfunction in abdominal sepsis.
- 2013
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In: Infection and Immunity. - 1098-5522. ; 81:7, s. 2499-2506
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Journal article (peer-reviewed)abstract
- T-cell dysfunction increases susceptibility to infections in patients with sepsis. In the present study, we hypothesized that Rho-kinase signaling might regulate induction of T-cell dysfunction in abdominal sepsis. Male C57BL/6 mice were treated with the specific Rho-kinase inhibitor Y-27632 (5 mg/kg) prior to cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation and regulatory T-cells (CD4(+)CD25(+)Foxp3(+)) were determined by flow cytometry. Formation of IFN-γ and IL-4 in the spleen and plasma levels of HMBG1 and IL-6 were quantified by use of ELISA. It was found that CLP evoked apoptosis and decreased proliferation in splenic CD4 T-cells. Inhibition of Rho-kinase activity decreased apoptosis and enhanced proliferation of CD4 T-cells in septic animals. In addition, CLP-evoked induction of regulatory T-cells in the spleen was abolished by Rho-kinase inhibition. CLP reduced the levels of IFN-γ and IL-4 in the spleen. Pretreatment with Y-27632 inhibited the sepsis-induced decrease in IFN-γ but not IL-4 formation in the spleen. CLP increased plasma levels of HMGB1 by 20-fold and IL-6 by 19-fold. Inhibition of Rho-kinase decreased this CLP-evoked increase of HMGB1, IL-6 and IL-17 levels in the plasma by more than 60%, suggesting that Rho-kinase regulates systemic inflammation in sepsis. Moreover, we observed that pretreatment with Y-27632 abolished CLP-induced bacteremia. Together, our novel findings indicate that Rho-kinase is a powerful regulator of T-cell immune dysfunction in abdominal sepsis. Thus, targeting Rho-kinase signaling might be a useful strategy to improve T-cell immunity in patients with abdominal sepsis.
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| 2. |
- Lepsenyi, Mattias, et al.
(author)
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CXCL2-CXCR2 axis mediates αV integrin-dependent peritoneal metastasis of colon cancer cells
- 2021
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In: Clinical and Experimental Metastasis. - : Springer Science and Business Media LLC. - 1573-7276 .- 0262-0898. ; 38:4, s. 401-410
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Journal article (peer-reviewed)abstract
- Peritoneal metastasis is an insidious aspect of colorectal cancer. The aim of the present study was to define mechanisms regulating colon cancer cell adhesion and spread to peritoneal wounds after abdominal surgery. Mice was laparotomized and injected intraperitoneally with CT-26 colon carcinoma cells and metastatic noduli in the peritoneal cavity was quantified after treatment with a CXCR2 antagonist or integrin-αV-antibody. CT-26 cells expressed cell surface chemokine receptors CXCR2, CXCR3, CXCR4 and CXCR5. Stimulation with the CXCR2 ligand, CXCL2, dose-dependently increased proliferation and migration of CT-26 cells in vitro. The CXCR2 antagonist, SB225002, dose-dependently decreased CXCL2-induced proliferation and migration of colon cancer cells in vitro. Intraperitoneal administration of CT-26 colon cancer cells resulted in wide-spread growth of metastatic nodules at the peritoneal surface of laparotomized animals. Laparotomy increased gene expression of CXCL2 at the incisional line. Pretreatment with CXCR2 antagonist reduced metastatic nodules by 70%. Moreover, stimulation with CXCL2 increased CT-26 cell adhesion to extracellular matrix (ECM) proteins in a CXCR2-dependent manner. CT-26 cells expressed the αV, β1 and β3 integrin subunits and immunoneutralization of αV abolished CXCL2-triggered adhesion of CT-26 to vitronectin, fibronectin and fibrinogen. Finally, inhibition of the αV integrin significantly attenuated the number of carcinomatosis nodules by 69% in laparotomized mice. These results were validated by use of the human colon cancer cell line HT-29 in vitro. Our data show that colon cancer cell adhesion and growth on peritoneal wound sites is mediated by a CXCL2-CXCR2 signaling axis and αV integrin-dependent adhesion to ECM proteins.
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| 3. |
- Zhang, Su, et al.
(author)
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Simvastatin protects against T cell immune dysfunction in abdominal sepsis.
- 2012
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In: Shock. - 1540-0514. ; 38:5, s. 524-531
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Journal article (peer-reviewed)abstract
- ABSTRACT: Sepsis-triggered immune paralysis including T-cell dysfunction increases susceptibility to infections. Statins exert beneficial effects in patients with sepsis, although the mechanisms remain elusive. Herein, we hypothesized that simvastatin may attenuate T-cell dysfunction in abdominal sepsis. Male C57BL/6 mice were pretreated with simvastatin (10 mg/kg) before cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation, and regulatory T cells (CD4CD25Foxp3) were quantified by use of flow cytometry. Formation of interferon γ (IFN-γ) and interleukin 4 (IL-4) in the spleen and plasma levels of high-mobility box group 1 (HMBG1) and IL-6 were determined using enzyme-linked immunosorbent assay. Cecal ligation and puncture caused a clear-cut increase in apoptosis and decrease in proliferation in splenic CD4 T cells. It was found that simvastatin markedly reduced apoptosis and improved proliferation in CD4 T cells in septic mice. Moreover, CLP-induced formation of regulatory T cells in the spleen was abolished in simvastatin-treated animals. Cecal ligation and puncture greatly decreased the levels of IFN-γ and IL-4 in the spleen. Simvastatin completely reversed this sepsis-mediated inhibition of IFN-γ and IL-4 formation in the spleen. We observed that CLP increased plasma levels of HMBG1 by 25-fold and IL-6 by 99,595-fold. Notably, treatment with simvastatin abolished this CLP-evoked increase in HMBG1 and IL-6 levels in the plasma, suggesting that simvastatin is a potent inhibitor of systemic inflammation in sepsis. Lastly, it was found that simvastatin reduced CLP-induced bacteremia. In conclusion, these novel findings suggest that simvastatin is a powerful regulator of T-cell immune dysfunction in abdominal sepsis. Thus, these protective effects of simvastatin on T-cell functions help to explain the protective effect of statins in patients with sepsis.
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