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Immunotolerant p50/NF?B Signaling and Attenuated Hepatic IFN? Expression Increases Neonatal Sensitivity to Endotoxemia.

ABSTRACT: Sepsis is a major cause of neonatal morbidity and mortality. The current paradigm suggests that neonatal susceptibility to infection is explained by an innate immune response that is functionally immature. Recent studies in adults have questioned a therapeutic role for IFN? in sepsis; however, the role of IFN? in mediating neonatal sensitivity to sepsis is unknown. We evaluated the transcriptional regulation and expression of IFN? in early neonatal (P0) and adult murine models of endotoxemia (IP LPS, 5 mg/kg). We found that hepatic, pulmonary, and serum IFN? expression was significantly attenuated in endotoxemic neonates when compared to similarly exposed adults. Furthermore, endotoxemia induced hepatic p65/NF?B and IRF3 activation exclusively in adults. In contrast, endotoxemia induced immunotolerant p50/NF?B signaling in neonatal mice without evidence of IRF3 activation. Consistent with impaired IFN? expression and attenuated circulating serum levels, neonatal pulmonary STAT1 signaling and target gene expression was significantly lower than adult levels. Using multiple in vivo approaches, the source of hepatic IFN? expression in endotoxemic adult mice was determined to be the hepatic macrophage, and experiments in RAW 264.7 cells confirmed that LPS-induced IFN? expression was NF?B dependent. Finally, treating neonatal mice with IFN? 2 h after endotoxemia stimulated pulmonary STAT1 signaling and STAT1 dependent gene expression. Furthermore, IFN? treatment of endotoxemic neonatal animals resulted in significantly improved survival following exposure to lethal endotoxemia. In conclusion, endotoxemia induced IFN? expression is attenuated in the early neonatal period, secondary to impaired NF?B-p65/IRF3 signaling. Pre-treatment with IFN? decreases neonatal sensitivity to endotoxemia. These results support further study of the role of impaired IFN? expression and neonatal sensitivity to sepsis.

SUBMITTER: McKenna S

PROVIDER: S-EPMC6168645 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Immunotolerant p50/NFκB Signaling and Attenuated Hepatic IFNβ Expression Increases Neonatal Sensitivity to Endotoxemia.

McKenna Sarah S Burey Taylor T Sandoval Jeryl J Nguyen Leanna L Castro Odalis O Gudipati Suma S Gonzalez Jazmin J El Kasmi Karim C KC Wright Clyde J CJ

Frontiers in immunology 20180926

Sepsis is a major cause of neonatal morbidity and mortality. The current paradigm suggests that neonatal susceptibility to infection is explained by an innate immune response that is functionally immature. Recent studies in adults have questioned a therapeutic role for IFNβ in sepsis; however, the role of IFNβ in mediating neonatal sensitivity to sepsis is unknown. We evaluated the transcriptional regulation and expression of IFNβ in early neonatal (P0) and adult murine models of endotoxemia (IP ...[more]

PMID: 30319651

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Project description:The unregulated activation of nuclear factor-κB (NF-κB) is a critical event in the progression of various inflammatory diseases such as ulcerative colitis, asthma, rheumatoid arthritis, bacterial induced gastritis, etc. Hence, blocking the transcriptional activity of NF-κB is a promising strategy towards the development of an anti-inflammatory agent. In this study, an integrated molecular and quantum mechanical approach was carried out to find a new potent andrographolide (AGP)-based analog that can inhibit DNA binding to NF-κB p50 and manifest anti-inflammatory activity. Our approach includes multiple sequence alignment, virtual screening, molecular docking (protein-ligand and protein-DNA), in silico site-directed mutagenesis, ADMET prediction, DFT (HOMO, LUMO, HLG, and EPM energy) analysis, MD simulation, and MM/GBSA rescoring. The virtual screening analysis of 237 AGP analogs yielded the five lead compounds based on the binding affinity. Further, molecular interactive docking and ADMET prediction of hit analogs revealed that Ana2 ((3Z,4S)-3-[2-[(4aR,6aS,7R,10aS,10bR)-3,3,6a,10b-tetramethyl-8-methylidene-1,4a,5,6,7,9,10,10a-octahydronaphtho[2,1-d][1,3]dioxin-7-yl]ethylidene]-4-hydroxyoxolan-2-one) is the most potent moiety as it displays the strongest binding affinity and better molecular/pharmacokinetic features. Moreover, DFT, MD simulation, and MM/GBSA studies corroborated the docking results and demonstrated better chemical and dynamic stability with the least binding free energy (- 29.99 kcal/mol) for the Ana2. Site-directed mutagenesis investigation (Cys62Ala) establishes the importance of the Cys62 amino acid residue towards the binding interaction and stability of Ana2 with NF-κB p50. Overall, the identified NF-κB p50 inhibitor opens up a new research horizon towards the development of plant-based anti-inflammatory drugs to combat progressive inflammatory diseases.Supplementary informationThe online version contains supplementary material available at 10.1007/s13205-022-03431-9.

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Immunotolerant p50/NF?B Signaling and Attenuated Hepatic IFN? Expression Increases Neonatal Sensitivity to Endotoxemia.

Publications

Immunotolerant p50/NFκB Signaling and Attenuated Hepatic IFNβ Expression Increases Neonatal Sensitivity to Endotoxemia.

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