Simvastatin protects against T cell immune dysfunction in abdominal sepsis.

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Simvastatin protects against T cell immune dysfunction in abdominal sepsis. / Zhang, Su; Luo, Lingtao; Wang, Yongzhi; Rahman, Milladur; Lepsenyi, Mattias; Syk, Ingvar; Jeppsson, Bengt; Thorlacius, Henrik.

I: Shock, Vol. 38, Nr. 5, 2012, s. 524-531.

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T1 - Simvastatin protects against T cell immune dysfunction in abdominal sepsis.

AU - Zhang, Su

AU - Luo, Lingtao

AU - Wang, Yongzhi

AU - Rahman, Milladur

AU - Lepsenyi, Mattias

AU - Syk, Ingvar

AU - Jeppsson, Bengt

AU - Thorlacius, Henrik

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1097/SHK.0b013e31826fb073

DO - 10.1097/SHK.0b013e31826fb073

M3 - Article

VL - 38

SP - 524

EP - 531

JO - Shock

JF - Shock

SN - 1540-0514

IS - 5

ER -