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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

352 Scopus citations

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 - 1 Apr 1999
Externally publishedYes

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