title: 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.affiliation: Division of Infectious Diseases and Immunology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and.
authors.forename: Gantsetseg
authors.initials: G
authors.lastname: Tumurkhuu
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and.
authors.forename: Jargalsaikhan
authors.initials: J
authors.lastname: Dagvadorj
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Heather D
authors.initials: HD
authors.lastname: Jones
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and.
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Crother
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and moshe.arditi@cshs.org.
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology; D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011014:Pneumonia / Q000235:genetics* / Q000276:immunology*; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014162:Transfection
chemical_list: C495377:LY96 protein, human; D051218:Lymphocyte Antigen 96; D020033:Protein Isoforms; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4