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 benefic ial by down-regulating the accompanying inflammation. Alternatively, apopto sis may be detrimental by impairing host defense, We studied whether Bcl-2, a potent antiapoptotic protein, could prevent lymphocyte apoptosis in a cl inically relevant model of sepsis, Transgenic mice in which Bcl-2 was overe xpressed in T cells had complete protection against sepsis-induced T lympho cyte apoptosis in thymus and spleen, Surprisingly, there was also a decreas e in splenic B cell apoptosis in septic Bcl-7 overexpressors compared with septic HeJ and HeOuJ mice. There were marked increases in TNF-alpha, IL-1 b eta, 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. Mitrotracker, a mitochondrial membrane potential indicator, de monstrated a sepsis-induced loss of membrane potential in T cells in HeJ an d HeOuJ mice but not in Bcl-2 mice, Importantly, Bcl-2 overexpressors also had improved survival in sepsis, To investigate the potential impact of los s 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 d ecreased survival compared with immunologically normal mice with sepsis, We conclude that overexpression of Bcl-2 provides protection against cell dea th in sepsis, Lymphocyte death may be detrimental in sepsis by compromising host defense.