Over-Expression of Bcl-2 Provides Protection in Septic Mice by a trans Effect

Abstract

Transgenic mice that over-express B cell leukemia/lymphomas (Bcl)-2 in myeloid cells under control of the human MRP8 promoter (hMRP8-Bcl-2) or in T lymphocytes under the Eμ promoter (Eμ-Bcl-2) were compared with C57BL/6 control mice following cecal ligation and puncture (CLP). There was a significant difference in outcome between the hMRP8-Bcl-2 and control mice with 100% survival in the hMRP8-Bcl-2 mice vs 25% survival in the control mice. In separate experiments there was a significant difference between Eμ-Bcl-2 and control mice with 87.5 and 22.2% survival, respectively. Adoptive transfer of CD11b-positive bone marrow cells from hMRP8-Bcl-2 or C57BL/6 mice to C57BL/6 mice subjected to CLP resulted in 100 and 0% survival, respectively. Adoptive transfer of CD11b-positive cells from either hMRP8-Bcl-2 or C57BL/6 mice to Rag-1−/− mice (no mature T or B cells) subjected to CLP resulted in survival of 87.5 and 12.5%, respectively. The hMRP8-Bcl-2 mice had significantly more neutrophils and fewer bacteria in the peritoneum compared with C57BL/6 mice 24 h after CLP. These experiments show that Bcl-2 over-expression is protective in CLP and that protection is independent of lymphocytes. We propose that over-expression of Bcl-2 in T cells or myeloid cells induce release of a molecule(s) that protects against death following CLP.

Adoptive transfer of dying cells causes bystander-induced apoptosis

“…In like fashion, there was a decrease in sepsis-induced T cell death in transgenic mice whose B cells over expressed Bcl-2. In accordance with our results, Iwata et al reported that mice which were transgenic for Bcl-2 in their myeloid-derived cells had decreased sepsis-induced apoptosis in their intestinal epithelial cells [8]. The mechanism of this cross-protection is unknown but has been reported by other groups [5][6][7][8][9][10].…”

“…A surprising finding in studies involving apoptosis has been the observation that protection against cell death in a particular type of cell can confer protection in a different phenotypic cell. This type of "cross-protection" of adjacent cells has been reported by several groups, and has prompted some investigators to propose a "neighborhood" theory in which cell survival is dependent upon "cross talk" from neighboring cells [8,9]. Although several growth factors and cytokines act in an autocrine/paracrine fashion, it remains to be elucidated which factors are responsible for promoting cell survival in neighboring cells.…”

“…Several independent investigative groups have demonstrated the remarkable ability of the antiapoptotic protein Bcl-2 to prevent sepsis-induced cell death [7][8][9]. Furthermore, overexpression of Bcl-2 in either T or B lymphocytes also protected against cell death in neighboring nonBcl-2 over expressing cells [6,7].…”

Role of programmed cell death in the immunopathogenesis of sepsis

“…Using a model of hemorrhagic shock followed by polymicrobial sepsis, Perl et al found that prolonging the lifespan of neutrophils did not exacerbate acute lung injury but provided an initial survival benefit in response to sepsis [50]. This is in line with previous studies indicating that during polymicrobial sepsis the presence of neutrophils with prolonged lifespan actually proved beneficial to outcome [51]; this stands in direct contrast to having a detrimental impact on the animals' survival in an inflammatory/ non-infectious environment [50]. Together these data imply that the tissue environment, which the neutrophil encounters, plays a major role in determining if the neutrophil mediates organ damage or not.…”

CD11c+ Dendritic Cells Are Required for Survival in Murine Polymicrobial Sepsis

“…Treatment of septic mice with caspase-3 inhibitors prevents mortality, although these studies could not identify the cellular target for the inhibition of apoptosis (8). We and others have shown that improved survival to severe sepsis induced by CLP could be seen in transgenic mice whose lymphocytes were overexpressing the antiapoptotic protein BCL-2 (8,23,24). In these animals, the increased loss of apoptotic T cells was prevented, and mortality was subsequently reduced.…”