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The role of the E2F1 transcription factor in the innate immune response to systemic LPS.

ABSTRACT: 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.

SUBMITTER: Warg LA

PROVIDER: S-EPMC4587596 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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The role of the E2F1 transcription factor in the innate immune response to systemic LPS.

Warg Laura A LA Oakes Judy L JL Burton Rachel R Neidermyer Amanda J AJ Rutledge Holly R HR Groshong Steve S Schwartz David A DA Yang Ivana V IV

American journal of physiology. Lung cellular and molecular physiology 20120615 5

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-/-) compar ...[more]

PMID: 22707615

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Project description:Fibroblast growth factor-23 (FGF-23) is a bone-derived hormone that activates FGFR/?-Klotho binary complexes in the kidney renal tubules to regulate phosphate reabsorption and vitamin D metabolism. The objective of this review is to discuss the emerging data that show that FGF-23 has functions beyond regulation of mineral metabolism, including roles in innate immune and hemodynamic responses. Excess FGF-23 is associated with inflammation and adverse infectious outcomes, as well as increased morbidity and mortality, particularly in patients with chronic kidney disease. Enhancer elements in the FGF-23 promoter have been identified that mediate the effects of inflammatory cytokines to stimulate FGF-23 gene transcription in bone. In addition, inflammation induces ectopic expression of FGF-23 and ?-Klotho in macrophages that do not normally express FGF-23 or its binary receptor complexes. These observations suggest that FGF-23 may play an important role in regulating innate immunity through multiple potential mechanisms. Circulating FGF-23 acts as a counter-regulatory hormone to suppress 1,25D production in the proximal tubule of the kidney. Since vitamin D deficiency may predispose infectious and cardiovascular diseases, FGF-23 effects on innate immune responses may be due to suppression of 1,25D production. Alternatively, systemic and locally produced FGF-23 may modulate immune functions through direct interactions with myeloid cells, including macrophages and polymorphonuclear leukocytes to impair immune cell functions. Short-acting small molecules that reversibly inhibit FGF-23 offer the potential to block pro-inflammatory and cardiotoxic effects of FGF-23 with less side effects compared with FGF-23 blocking antibodies that have the potential to cause hyperphosphatemia and soft tissue calcifications in animal models. In conclusion, there are several mechanisms by which FGF-23 impacts the innate immune system and further investigation is critical for the development of therapies to treat diseases associated with elevated FGF-23.

Dataset Information

The role of the E2F1 transcription factor in the innate immune response to systemic LPS.

Publications

The role of the E2F1 transcription factor in the innate immune response to systemic LPS.

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