Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis.
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-alpha, IL-1beta, and IL-10 in thymic tissue in sepsis in the three species of mice, and the increase in TNF-alpha 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.
Hotchkiss
R S
RS
Department of Anesthesiology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA. hotch@morpheus.wustl.edu
Swanson
P E
PE
Knudson
C M
CM
Chang
K C
KC
Cobb
J P
JP
Osborne
D F
DF
Zollner
K M
KM
Buchman
T G
TG
Korsmeyer
S J
SJ
Karl
I E
IE
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004396:Coloring Agents; D004587:Electrophoresis, Agar Gel; D004801:Eosine Yellowish-(YS); D005434:Flow Cytometry; D006416:Hematoxylin; D020287:In Situ Nick-End Labeling; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics*; D018805:Sepsis / Q000401:mortality* / Q000473:pathology*; D015996:Survival Rate
D004396:Coloring Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D004801:Eosine Yellowish-(YS); D006416:Hematoxylin