TAT-BH4 and TAT-Bcl-xL Peptides Protect against Sepsis-Induced Lymphocyte Apoptosis In Vivo

Abstract

Apoptosis is a key pathogenic mechanism in sepsis that induces extensive death of lymphocytes and dendritic cells, thereby contributing to the immunosuppression that characterizes the septic disorder. Numerous animal studies indicate that prevention of apoptosis in sepsis improves survival and may represent a potential therapy for this highly lethal disorder. Recently, novel cell-penetrating peptide constructs such as HIV-1 TAT basic domain and related peptides have been developed to deliver bioactive cargoes and peptides into cells. In the present study, we investigated the effects of sepsis-induced apoptosis in Bcl-xL transgenic mice and in wild-type mice treated with an antiapoptotic TAT-Bcl-xL fusion protein and TAT-BH4 peptide. Lymphocytes from Bcl-xL transgenic mice were resistant to sepsis-induced apoptosis, and these mice had a ∼3-fold improvement in survival. TAT-Bcl-xL and TAT-BH4 prevented Escherichia coli-induced human lymphocyte apoptosis ex vivo and markedly decreased lymphocyte apoptosis in an in vivo mouse model of sepsis. In conclusion, TAT-conjugated antiapoptotic Bcl-2-like peptides may offer a novel therapy to prevent apoptosis in sepsis and improve survival.

Adoptive transfer of dying cells causes bystander-induced apoptosis

“…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]. Iwata et al speculated, however, that the protective action of Bcl-2 over expressing cells was via a "trans" effect, i.e., Bcl-2 over expressing cells released an unknown cytoprotective factor which prevented death in non-Bcl-2 over expressing cells of distinct and distant lineages.…”

Identification of a Novel Cell-Penetrating Peptide from Human Phosphatidate Phosphatase LpIN3

“…Many therapeutic cargo molecules have been successfully delivered into cells via CPPs including proteins, peptides, si-RNA, DNA, and others (van den Berg and Dowdy, 2011;Zorko and Langel, 2005). TAT-BH4 and TAT-Bcl-XL inhibited sepsis-induced apoptosis of lymphocytes in vivo (Hotchkiss et al, 2006) and TAT-Cre was used to generate conditional knock-out mice (Wadia et al, 2004). Polyarginine (11R)-conjugated VIVIT peptide, which is a specific NFAT inhibitory peptide, was able to inhibit graft rejection of allogeneic islet transplantation in mice (Noguchi et al, 2004).…”

Role of programmed cell death in the immunopathogenesis of sepsis

“…The cell membrane permeable TAT-Bcl-X L peptide construct as well as a TAT-conjugated peptide of the anti-apoptotic BH4 domain of Bcl-X L (TAT-BH4) decreased sepsis-induced splenocyte T-and B-cell apoptosis to near sham levels in experimental murine sepsis. TAT-Bcl-X L prevented Escherichia coli-induced human lymphocyte apoptosis ex vivo and markedly decreased lymphocyte apoptosis in an in vivo mouse model of sepsis [58].…”