title: Rho kinase regulates induction of T-cell immune dysfunction in abdominal sepsis.
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 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.
authors: Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Lund, Sweden.
authors: Z
authors: Z
authors: Hasan
authors: K
authors: K
authors: Palani
authors: S
authors: S
authors: Zhang
authors: M
authors: M
authors: Lepsenyi
authors: R
authors: R
authors: Hwaiz
authors: M
authors: M
authors: Rahman
authors: I
authors: I
authors: Syk
authors: B
authors: B
authors: Jeppsson
authors: Henrik
authors: H
authors: Thorlacius
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D058491:Bacterial Load; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002432:Cecum / Q000276:immunology / Q000293:injuries / Q000503:physiopathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D024243:HMGB1 Protein / Q000097:blood; D007111:Immunity, Cellular; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D020381:Interleukin-17 / Q000097:blood; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000494:pharmacology; D018805:Sepsis / Q000201:enzymology / Q000382:microbiology / Q000503:physiopathology*; D013154:Spleen / Q000473:pathology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000577:Amides; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D024243:HMGB1 Protein; C508018:Il2ra protein, mouse; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D011725:Pyridines; C108830:Y 27632; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases
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