Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis

Richard S. Hotchkiss, Paul E. Swanson, C. Michael Knudson, Katherine C. Chang, J. Perren Cobb, Dale F. Osborne, Kimberly M. Zollner, Timothy G. Buchman, Stanley J. Korsmeyer, Irene E. Karl

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Abstract

In sepsis there is extensive apoptosis of lymphocytes, which may be beneficial by down-regulating the accompanying inflammation. Alternatively, apoptosis may be detrimental by impairing host defense. We studied whether Bcl-2, a potent antiapoptotic protein, could prevent lymphocyte apoptosis in a clinically relevant model of sepsis. Transgenic mice in which Bcl-2 was overexpressed in T cells had complete protection against sepsis-induced T lymphocyte apoptosis in thymus and spleen. Surprisingly, there was also a decrease in splenic B cell apoptosis in septic Bcl-2 overexpressors compared with septic HeJ and HeOuJ mice. There were marked increases in TNF-α, IL- 1β, and IL-10 in thymic tissue in sepsis in the three species of mice, and the increase in TNF-α and IL-10 in HeOuJ mice was greater than that in Bcl- 2 mice. Mitotracker, a mitochondrial membrane potential indicator, demonstrated a sepsis-induced loss of membrane potential in T cells in HeJ and HeOuJ mice but not in Bcl-2 mice. Importantly, Bcl-2 overexpressors also had improved survival in sepsis. To investigate the potential impact of loss of lymphocytes on survival in sepsis, Rag-1(-/-) mice, which are totally deficient in mature T and B cells, were also studied. Rag-1(-/-) mice had decreased survival compared with immunologically normal mice with sepsis. We conclude that overexpression of Bcl-2 provides protection against cell death in sepsis. Lymphocyte death may be detrimental in sepsis by compromising host defense.

Original languageEnglish
Pages (from-to)4148-4156
Number of pages9
JournalJournal of Immunology
Volume162
Issue number7
StatePublished - Apr 1 1999

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    Hotchkiss, R. S., Swanson, P. E., Knudson, C. M., Chang, K. C., Cobb, J. P., Osborne, D. F., Zollner, K. M., Buchman, T. G., Korsmeyer, S. J., & Karl, I. E. (1999). Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. Journal of Immunology, 162(7), 4148-4156.