Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human lymphocyte response to E. coli to identify any transcriptional component to the protection in vitro bacterially induced PBMC apoptosis

ABSTRACT: Sepsis induces lymphocyte apoptosis which can be prevented by over-expression of anti-apoptotic Bcl-2 family members. The anti-apoptotic activity of Bcl-2 family members is localized in the BH4 domain. The therapeutic peptide, TAT-BH4, was found to prevent sepsis-induced lymphocyte apoptosis in vivo. We also showed that this peptide prevents PBMC apoptosis in response to bacterial exudate. Here we studied whether there was a transcriptional component to that protection in vitro in bacterially-induced PBMC apoptosis.

ORGANISM(S): Homo sapiens

SUBMITTER: David Piwnica-Worms

PROVIDER: E-MEXP-555 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

TAT-BH4 and TAT-Bcl-xL peptides protect against sepsis-induced lymphocyte apoptosis in vivo.

Hotchkiss Richard S RS McConnell Kevin W KW Bullok Kristin K Davis Christopher G CG Chang Katherine C KC Schwulst Steven J SJ Dunne Jeffrey C JC Dietz Gunnar P H GP Bähr Mathias M McDunn Jonathan E JE Karl Irene E IE Wagner Tracey H TH Cobb J Perren JP Coopersmith Craig M CM Piwnica-Worms David D

Journal of immunology (Baltimore, Md. : 1950) 20060501 9

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 bio ...[more]

PMID: 16622015

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Project description:Background: We hypothesized that spleen microarray gene expression profiles analyzed with contemporary pathway analysis software would provide molecular pathways of interest and target genes that might help explain the affect of bcl-2 on improving survival during sepsis. Methods: Two mouse models of sepsis, cecal ligation and puncture and tracheal instillation of Pseudomonas aeruginosa, were tested in both wild-type mice and mice that overexpress bcl-2. Whole spleens were obtained 6 hours after septic injury. DNA microarray transcriptional profiles were obtained using the Affymetrix 430A GeneChip, containing 22,690 elements. Ingenuity Pathway Analysis software was used to construct hypothetical transcriptional networks that changed in response to sepsis and expression of the bcl-2 transgene. Results: A conservative approach was used wherein only changes induced by both abdominal and pulmonary sepsis were studied. At 6 hours, sepsis induced alterations in the abundance of hundreds of spleen genes, including a number of proinflammatory mediators (e.g., IL-6). These sepsis-induced alterations were blocked by expression of the bcl-2 transgene. Network analysis implicated a number of bcl-2-related apoptosis genes, including bcl2L11 (bim), bcl-2L2 (bcl-w), bmf, and mcl-1. Sepsis in bcl-2 transgenic animals resulted in alteration of RNA abundance for only a single gene, ceacam1. Conclusion: These findings are consistent with sepsis-induced alterations in the balance of pro- and anti-apoptotic transcriptional networks. In addition, our data suggest that the ability of bcl-2 overexpression to improve survival in sepsis in this model is related in part to prevention of sepsis-induced alterations in spleen transcriptional responses. Experiment Overall Design: To determine the splenic response in these lethal models of CLP and Pseudomonas pneumonia, microarray analysis was performed on each spleen harvested from wild-type animals 6 hours after CLP or tracheal instillation of bacteria. The responses of the CLP or Pseudomonas spleens were compared concurrently to those of the wild-type controls, sham laparotomy and tracheal instillation of saline, respectively. This study was repeated in animals overexpressing bcl-2. Thus, the splenocyte effect of sepsis secondary to CLP (n=6) or Pseudomonas pneumonia (n=5) could be determined compared to their controls (n=6 and 5, respectively), and the effect of bcl-2 overexpression in turn also could be determined in both CLP (n=5) and pneumonia models (n=5) compared to controls (n=5 and 5, respectively).

Dataset Information

Transcription profiling of human lymphocyte response to E. coli to identify any transcriptional component to the protection in vitro bacterially induced PBMC apoptosis

Publications

TAT-BH4 and TAT-Bcl-xL peptides protect against sepsis-induced lymphocyte apoptosis in vivo.

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