title: Simvastatin protects against T cell immune dysfunction in abdominal sepsis.
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.
authors.affiliation: Department of Clinical Sciences, Malmö, Section for Surgery, Malmö, Lund University, Sweden.
authors.forename: Su
authors.initials: S
authors.lastname: Zhang
authors.forename: Lingtao
authors.initials: L
authors.lastname: Luo
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Wang
authors.forename: Milladur
authors.initials: M
authors.lastname: Rahman
authors.forename: Mattias
authors.initials: M
authors.lastname: Lepsenyi
authors.forename: Ingvar
authors.initials: I
authors.lastname: Syk
authors.forename: Bengt
authors.initials: B
authors.lastname: Jeppsson
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000276:immunology; D024243:HMGB1 Protein / Q000097:blood / Q000276:immunology; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018805:Sepsis / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D019821:Simvastatin / Q000494:pharmacology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D016207:Cytokines; D024243:HMGB1 Protein; D019821:Simvastatin