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Infect Immun. 2013 Jul;81(7):2499-506. doi: 10.1128/IAI.00126-13. Epub 2013 Apr 29.

Rho kinase regulates induction of T-cell immune dysfunction in abdominal sepsis.

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  • 1Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Lund, Sweden.


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 of body weight) prior to cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation, and percentage of regulatory T cells (CD4(+) CD25(+) Foxp3(+)) were determined by flow cytometry. Formation of gamma interferon (IFN-γ) and interleukin 4 (IL-4) in the spleen and plasma levels of HMBG1, IL-17, and IL-6 were quantified by use of enzyme-linked immunosorbent assay (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 high-mobility group box 1 (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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