Over-expression of Bcl-2 provides protection in septic mice by a trans effect.
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 E micro promoter (E micro -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 E micro -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.
Iwata
Akiko
A
Department of Surgery and Medicine, University of Washington, Seattle, WA 98104, USA. aiwata@u.washington.edu
Stevenson
Vicki Morgan
VM
Minard
Annie
A
Tasch
Michael
M
Tupper
Joan
J
Lagasse
Eric
E
Weissman
Irving
I
Harlan
John M
JM
Winn
Robert K
RK
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001202:Ascitic Fluid / Q000235:genetics / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D016026:Bone Marrow Transplantation / Q000276:immunology; D039481:CD11b Antigen / Q000096:biosynthesis; D002432:Cecum; D015169:Colony Count, Microbial; D016207:Cytokines / Q000032:analysis; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D007958:Leukocyte Count; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism; D010533:Peritoneal Lavage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D011677:Punctures; D018805:Sepsis / Q000235:genetics* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000378:metabolism
D039481:CD11b Antigen; D016207:Cytokines; D018398:Homeodomain Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C064658:RAG-1 protein