Distamycin A Inhibits HMGA1-Binding to the P-Selectin Promoter and Attenuates Lung and Liver Inflammation during Murine Endotoxemia

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dc.contributor.author Baron, Rebecca M. en_US
dc.contributor.author Lopez-Guzman, Silvia en_US
dc.contributor.author Riascos, Dario F. en_US
dc.contributor.author Macias, Alvaro A. en_US
dc.contributor.author Layne, Matthew D. en_US
dc.contributor.author Cheng, Guiying en_US
dc.contributor.author Harris, Cailin en_US
dc.contributor.author Chung, Su Wol en_US
dc.contributor.author Reeves, Raymond en_US
dc.contributor.author von Andrian, Ulrich H. en_US
dc.contributor.author Perrella, Mark A. en_US
dc.date.accessioned 2012-01-11T21:40:13Z
dc.date.available 2012-01-11T21:40:13Z
dc.date.issued 2010-5-14 en_US
dc.identifier.citation Baron, Rebecca M., Silvia Lopez-Guzman, Dario F. Riascos, Alvaro A. Macias, Matthew D. Layne, Guiying Cheng, Cailin Harris, Su Wol Chung, Raymond Reeves, Ulrich H. von Andrian, Mark A. Perrella. "Distamycin A Inhibits HMGA1-Binding to the P-Selectin Promoter and Attenuates Lung and Liver Inflammation during Murine Endotoxemia" PLoS ONE 5(5): e10656. (2010) en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://hdl.handle.net/2144/3228
dc.description.abstract BACKGROUND. The architectural transcription factor High Mobility Group-A1 (HMGA1) binds to the minor groove of AT-rich DNA and forms transcription factor complexes ("enhanceosomes") that upregulate expression of select genes within the inflammatory cascade during critical illness syndromes such as acute lung injury (ALI). AT-rich regions of DNA surround transcription factor binding sites in genes critical for the inflammatory response. Minor groove binding drugs (MGBs), such as Distamycin A (Dist A), interfere with AT-rich region DNA binding in a sequence and conformation-specific manner, and HMGA1 is one of the few transcription factors whose binding is inhibited by MGBs. OBJECTIVES. To determine whether MGBs exert beneficial effects during endotoxemia through attenuating tissue inflammation via interfering with HMGA1-DNA binding and modulating expression of adhesion molecules. METHODOLOGY/PRINCIPAL FINDINGS. Administration of Dist A significantly decreased lung and liver inflammation during murine endotoxemia. In intravital microscopy studies, Dist A attenuated neutrophil-endothelial interactions in vivo following an inflammatory stimulus. Endotoxin induction of P-selectin expression in lung and liver tissue and promoter activity in endothelial cells was significantly reduced by Dist A, while E-selectin induction was not significantly affected. Moreover, Dist A disrupted formation of an inducible complex containing NF-?B that binds an AT-rich region of the P-selectin promoter. Transfection studies demonstrated a critical role for HMGA1 in facilitating cytokine and NF-?B induction of P-selectin promoter activity, and Dist A inhibited binding of HMGA1 to this AT-rich region of the P-selectin promoter in vivo. CONCLUSIONS/SIGNIFICANCE. We describe a novel targeted approach in modulating lung and liver inflammation in vivo during murine endotoxemia through decreasing binding of HMGA1 to a distinct AT-rich region of the P-selectin promoter. These studies highlight the ability of MGBs to function as molecular tools for dissecting transcriptional mechanisms in vivo and suggest alternative treatment approaches for critical illness. en_US
dc.description.sponsorship National Institutes of Health (AI054465, HL091957, AI061246, GM53249, HL60788) en_US
dc.language.iso en en_US
dc.publisher Public Library of Science en_US
dc.rights Baron et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. en_US
dc.title Distamycin A Inhibits HMGA1-Binding to the P-Selectin Promoter and Attenuates Lung and Liver Inflammation during Murine Endotoxemia en_US
dc.type article en_US
dc.identifier.doi 10.1371/journal.pone.0010656 en_US
dc.identifier.pubmedid 20498830 en_US
dc.identifier.pmcid 2871042 en_US

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