Rho-kinase regulates induction of T-cell immune dysfunction in abdominal sepsis.
(2013) In Infection and Immunity 81(7). p.2499-2506- 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) prior to cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation and regulatory T-cells (CD4(+)CD25(+)Foxp3(+)) were determined by flow cytometry. Formation of IFN-γ and IL-4 in the spleen and plasma levels of HMBG1 and IL-6 were quantified by use of 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... (More)
- 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) prior to cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation and regulatory T-cells (CD4(+)CD25(+)Foxp3(+)) were determined by flow cytometry. Formation of IFN-γ and IL-4 in the spleen and plasma levels of HMBG1 and IL-6 were quantified by use of 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 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3805158
- author
- Hasan, Zirak LU ; Palani, Karzan LU ; Zhang, Songen LU ; Lepsenyi, Mattias LU ; Hwaiz, Rundk LU ; Rahman, Milladur LU ; Syk, Ingvar LU ; Jeppsson, Bengt LU and Thorlacius, Henrik LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Infection and Immunity
- volume
- 81
- issue
- 7
- pages
- 2499 - 2506
- publisher
- American Society for Microbiology
- external identifiers
-
- wos:000320307300022
- pmid:23630965
- scopus:84879425079
- pmid:23630965
- ISSN
- 1098-5522
- DOI
- 10.1128/IAI.00126-13
- language
- English
- LU publication?
- yes
- id
- 321103fd-00f6-4de8-9346-57bdb37375ed (old id 3805158)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23630965?dopt=Abstract
- date added to LUP
- 2016-04-01 11:09:43
- date last changed
- 2022-04-20 17:33:48
@article{321103fd-00f6-4de8-9346-57bdb37375ed, 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) prior to cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation and regulatory T-cells (CD4(+)CD25(+)Foxp3(+)) were determined by flow cytometry. Formation of IFN-γ and IL-4 in the spleen and plasma levels of HMBG1 and IL-6 were quantified by use of 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 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.}}, author = {{Hasan, Zirak and Palani, Karzan and Zhang, Songen and Lepsenyi, Mattias and Hwaiz, Rundk and Rahman, Milladur and Syk, Ingvar and Jeppsson, Bengt and Thorlacius, Henrik}}, issn = {{1098-5522}}, language = {{eng}}, number = {{7}}, pages = {{2499--2506}}, publisher = {{American Society for Microbiology}}, series = {{Infection and Immunity}}, title = {{Rho-kinase regulates induction of T-cell immune dysfunction in abdominal sepsis.}}, url = {{http://dx.doi.org/10.1128/IAI.00126-13}}, doi = {{10.1128/IAI.00126-13}}, volume = {{81}}, year = {{2013}}, }