Alternatively spliced myeloid differentiation protein-2 inhibits TLR4-mediated lung inflammation.

Abstract

We previously identified a novel alternatively spliced isoform of human myeloid differentiation protein-2 (MD-2s) that competitively inhibits binding of MD-2 to TLR4 in vitro. In this study, we investigated the protective role of MD-2s in LPS-induced acute lung injury by delivering intratracheally an adenovirus construct that expressed MD-2s (Ad-MD-2s). After adenovirus-mediated gene transfer, MD-2s was strongly expressed in lung epithelial cells and readily detected in bronchoalveolar lavage fluid. Compared to adenovirus serotype 5 containing an empty vector lacking a transgene control mice, Ad-MD-2s delivery resulted in significantly less LPS-induced inflammation in the lungs, including less protein leakage, cell recruitment, and expression of proinflammatory cytokines and chemokines, such as IL-6, keratinocyte chemoattractant, and MIP-2. Bronchoalveolar lavage fluid from Ad-MD-2s mice transferred into lungs of naive mice before intratracheal LPS challenge diminished proinflammatory cytokine levels. As house dust mite (HDM) sensitization is dependent on TLR4 and HDM Der p 2, a structural homolog of MD-2, we also investigated the effect of MD-2s on HDM-induced allergic airway inflammation. Ad-MD-2s given before HDM sensitization significantly inhibited subsequent allergic airway inflammation after HDM challenge, including reductions in eosinophils, goblet cell hyperplasia, and IL-5 levels. Our study indicates that the alternatively spliced short isoform of human MD-2 could be a potential therapeutic candidate to treat human diseases induced or exacerbated by TLR4 signaling, such as Gram-negative bacterial endotoxin-induced lung injury and HDM-triggered allergic lung inflammation.

• Authors: Gantsetseg Tumurkhuu, Jargalsaikhan Dagvadorj, Heather D Jones, Shuang Chen, Kenichi Shimada, Timothy R Crother, Moshe Arditi
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 4 Pg. 1686-94 (Feb 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25576596 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• LY96 protein, human
• Lymphocyte Antigen 96
• Protein Isoforms
• Tlr4 protein, mouse
• Toll-Like Receptor 4

Topics

• Acute Lung Injury (genetics, immunology)
• Alternative Splicing
• Animals
• Blotting, Western
• Disease Models, Animal
• Female
• Flow Cytometry
• Humans
• Hypersensitivity (genetics, immunology)
• Immunohistochemistry
• Lymphocyte Antigen 96 (genetics, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Pneumonia (genetics, immunology)
• Protein Isoforms (genetics, immunology)
• Real-Time Polymerase Chain Reaction
• Toll-Like Receptor 4 (immunology)
• Transfection