Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia.

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-kappaB that binds an AT-rich region of the P-selectin promoter. Transfection studies demonstrated a critical role for HMGA1 in facilitating cytokine and NF-kappaB 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.

• Authors: Rebecca M Baron, 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
• Journal: PloS one (PLoS One) Vol. 5 Issue 5 Pg. e10656 (May 14 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20498830 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• Distamycins
• Endotoxins
• NF-kappa B
• P-Selectin
• HMGA1a Protein
• stallimycin

Topics

• AT Rich Sequence
• Animals
• Cattle
• Cell Communication (drug effects)
• Cytokines (metabolism)
• Distamycins (pharmacology, therapeutic use)
• Endothelial Cells (cytology, drug effects, metabolism)
• Endotoxemia (complications, drug therapy, pathology, prevention & control)
• Endotoxins
• HMGA1a Protein (metabolism)
• Humans
• Inflammation (complications, metabolism, pathology)
• Liver (drug effects, metabolism, pathology)
• Lung (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Neutrophils (cytology, drug effects, metabolism)
• P-Selectin (genetics, metabolism)
• Promoter Regions, Genetic
• Protein Binding (drug effects)