The role of the E2F1 transcription factor in the innate immune response to systemic LPS.
Previous publications from our and other groups identified E2F1 as a transcription factor involved in the regulation of inflammatory response to Toll-like receptor ligands including LPS. In this study, we challenged E2F1-deficient mice with LPS systemically and demonstrated decreased survival despite attenuated inflammatory response compared with controls. Gene expression profiling of liver tissue identified a dampened transcriptional response in the coagulation cascade in B6;129(E2F1-/-) compared with B6x129 F2 mice. These data were further corroborated by increased prothrombin time, activated partial thromboplastin time, and fibrin split products in the blood of E2F1-deficient mice, suggesting disseminated intravascular coagulation as a consequence of uncontrolled sepsis providing at least a partial explanation for their decreased survival despite attenuated inflammatory response. To identify novel miRNAs involved in the innate immune response to LPS, we also performed miRNA profiling of liver tissue from B6;129(E2F1-/-) and B6x129 F2 mice treated with LPS systemically. Our analysis identified a set of miRNAs and their mRNA targets that are significantly differentially regulated in E2F1-deficient but not control mice including let-7g, miR-101b, miR-181b, and miR-455. These miRNAs represent novel regulators of the innate immune response. In summary, we used transcriptional and miRNA profiling to characterize the response of E2F1-deficient mice to systemic LPS.
Univ. of Colorado Denver, Aurora, CO 80045, USA.
Laura A
LA
Warg
Judy L
JL
Oakes
Rachel
R
Burton
Amanda J
AJ
Neidermyer
Holly R
HR
Rutledge
Steve
S
Groshong
David A
DA
Schwartz
Ivana V
IV
Yang
D000818:Animals; D001665:Binding Sites; D001779:Blood Coagulation Factors / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013927:Thrombosis / Q000235:genetics
D001779:Blood Coagulation Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D008070:Lipopolysaccharides; C574091:MIRN455 microRNA, mouse; D035683:MicroRNAs; C542687:mirnlet7 microRNA, mouse