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IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis.
J Immunol. 2010 Feb 01; 184(3):1401-9.JI

Abstract

IL-15 is a pluripotent antiapoptotic cytokine that signals to cells of both the innate and adaptive immune system and is regarded as a highly promising immunomodulatory agent in cancer therapy. Sepsis is a lethal condition in which apoptosis-induced depletion of immune cells and subsequent immunosuppression are thought to contribute to morbidity and mortality. This study tested the ability of IL-15 to block apoptosis, prevent immunosuppression, and improve survival in sepsis. Mice were made septic using cecal ligation and puncture or Pseudomonas aeruginosa pneumonia. The experiments comprised a 2 x 2 full factorial design with surgical sepsis versus sham and IL-15 versus vehicle. In addition to survival studies, splenic cellularity, canonical markers of activation and proliferation, intracellular pro- and antiapoptotic Bcl-2 family protein expression, and markers of immune cell apoptosis were evaluated by flow cytometry. Cytokine production was examined both in plasma of treated mice and splenocytes that were stimulated ex vivo. IL-15 blocked sepsis-induced apoptosis of NK cells, dendritic cells, and CD8 T cells. IL-15 also decreased sepsis-induced gut epithelial apoptosis. IL-15 therapy increased the abundance of antiapoptotic Bcl-2 while decreasing proapoptotic Bim and PUMA. IL-15 increased both circulating IFN-gamma, as well as the percentage of NK cells that produced IFN-gamma. Finally, IL-15 increased survival in both cecal ligation and puncture and P. aeruginosa pneumonia. In conclusion, IL-15 prevents two immunopathologic hallmarks of sepsis, namely, apoptosis and immunosuppression, and improves survival in two different models of sepsis. IL-15 represents a potentially novel therapy of this highly lethal disorder.

Authors+Show Affiliations

Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20026737

Citation

Inoue, Shigeaki, et al. "IL-15 Prevents Apoptosis, Reverses Innate and Adaptive Immune Dysfunction, and Improves Survival in Sepsis." Journal of Immunology (Baltimore, Md. : 1950), vol. 184, no. 3, 2010, pp. 1401-9.
Inoue S, Unsinger J, Davis CG, et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J Immunol. 2010;184(3):1401-9.
Inoue, S., Unsinger, J., Davis, C. G., Muenzer, J. T., Ferguson, T. A., Chang, K., Osborne, D. F., Clark, A. T., Coopersmith, C. M., McDunn, J. E., & Hotchkiss, R. S. (2010). IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. Journal of Immunology (Baltimore, Md. : 1950), 184(3), 1401-9. https://doi.org/10.4049/jimmunol.0902307
Inoue S, et al. IL-15 Prevents Apoptosis, Reverses Innate and Adaptive Immune Dysfunction, and Improves Survival in Sepsis. J Immunol. 2010 Feb 1;184(3):1401-9. PubMed PMID: 20026737.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. AU - Inoue,Shigeaki, AU - Unsinger,Jacqueline, AU - Davis,Christopher G, AU - Muenzer,Jared T, AU - Ferguson,Thomas A, AU - Chang,Katherine, AU - Osborne,Dale F, AU - Clark,Andrew T, AU - Coopersmith,Craig M, AU - McDunn,Jonathan E, AU - Hotchkiss,Richard S, Y1 - 2009/12/21/ PY - 2009/12/23/entrez PY - 2009/12/23/pubmed PY - 2010/3/13/medline SP - 1401 EP - 9 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 184 IS - 3 N2 - IL-15 is a pluripotent antiapoptotic cytokine that signals to cells of both the innate and adaptive immune system and is regarded as a highly promising immunomodulatory agent in cancer therapy. Sepsis is a lethal condition in which apoptosis-induced depletion of immune cells and subsequent immunosuppression are thought to contribute to morbidity and mortality. This study tested the ability of IL-15 to block apoptosis, prevent immunosuppression, and improve survival in sepsis. Mice were made septic using cecal ligation and puncture or Pseudomonas aeruginosa pneumonia. The experiments comprised a 2 x 2 full factorial design with surgical sepsis versus sham and IL-15 versus vehicle. In addition to survival studies, splenic cellularity, canonical markers of activation and proliferation, intracellular pro- and antiapoptotic Bcl-2 family protein expression, and markers of immune cell apoptosis were evaluated by flow cytometry. Cytokine production was examined both in plasma of treated mice and splenocytes that were stimulated ex vivo. IL-15 blocked sepsis-induced apoptosis of NK cells, dendritic cells, and CD8 T cells. IL-15 also decreased sepsis-induced gut epithelial apoptosis. IL-15 therapy increased the abundance of antiapoptotic Bcl-2 while decreasing proapoptotic Bim and PUMA. IL-15 increased both circulating IFN-gamma, as well as the percentage of NK cells that produced IFN-gamma. Finally, IL-15 increased survival in both cecal ligation and puncture and P. aeruginosa pneumonia. In conclusion, IL-15 prevents two immunopathologic hallmarks of sepsis, namely, apoptosis and immunosuppression, and improves survival in two different models of sepsis. IL-15 represents a potentially novel therapy of this highly lethal disorder. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/20026737/IL_15_prevents_apoptosis_reverses_innate_and_adaptive_immune_dysfunction_and_improves_survival_in_sepsis_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=20026737 DB - PRIME DP - Unbound Medicine ER -