Simvastatin protects against T cell immune dysfunction in abdominal sepsis.
Zhang, Su LU ; Luo, Lingtao ; Wang, Yongzhi LU ; Rahman, Milladur LU
; Lepsenyi, Mattias
LU
; Syk, Ingvar
LU
; Jeppsson, Bengt
LU
and Thorlacius, Henrik
LU
(2012)
In Shock
38(5).
p.524-531
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3161009
- author
- Zhang, Su
LU
; Luo, Lingtao
; Wang, Yongzhi
LU
; Rahman, Milladur
LU
; Lepsenyi, Mattias
LU
; Syk, Ingvar
LU
; Jeppsson, Bengt
LU
and Thorlacius, Henrik
LU
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Shock
- volume
- 38
- issue
- 5
- pages
- 524 - 531
- publisher
- Lippincott Williams & Wilkins
- external identifiers
-
- wos:000310367500012
- pmid:23042198
- scopus:84868213148
- pmid:23042198
- ISSN
- 1540-0514
- DOI
- 10.1097/SHK.0b013e31826fb073
- language
- English
- LU publication?
- yes
- id
- 5472298b-aeb7-4573-9cc2-bfda443ff650 (old id 3161009)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23042198?dopt=Abstract
- date added to LUP
- 2016-04-04 08:56:58
- date last changed
- 2022-04-23 18:42:18
@article{5472298b-aeb7-4573-9cc2-bfda443ff650,
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.}},
author = {{Zhang, Su and Luo, Lingtao and Wang, Yongzhi and Rahman, Milladur and Lepsenyi, Mattias and Syk, Ingvar and Jeppsson, Bengt and Thorlacius, Henrik}},
issn = {{1540-0514}},
language = {{eng}},
number = {{5}},
pages = {{524--531}},
publisher = {{Lippincott Williams & Wilkins}},
series = {{Shock}},
title = {{Simvastatin protects against T cell immune dysfunction in abdominal sepsis.}},
url = {{http://dx.doi.org/10.1097/SHK.0b013e31826fb073}},
doi = {{10.1097/SHK.0b013e31826fb073}},
volume = {{38}},
year = {{2012}},
}