Identification of a novel human MD-2 splice variant that negatively regulates Lipopolysaccharide-induced TLR4 signaling
Michelsen, Kathrin S.
Sirois, Cherilyn M.
Crother, Timothy R.
Student AuthorsCherilyn M. Sirois
UMass Chan AffiliationsDepartment of Medicine, Division of Infectious Diseases and Immunology
Document TypeJournal Article
KeywordsCell Line; Cell Separation; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Humans; Immunoblotting; Immunoprecipitation; Interleukin-8; Lipopolysaccharides; Lymphocyte Antigen 96; Microscopy, Confocal; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Toll-Like Receptor 4
Immunology and Infectious Disease
Medicine and Health Sciences
MetadataShow full item record
AbstractMyeloid differentiation factor 2 (MD-2) is a secreted gp that assembles with TLR4 to form a functional signaling receptor for bacterial LPS. In this study, we have identified a novel alternatively spliced isoform of human MD-2, termed MD-2 short (MD-2s), which lacks the region encoded by exon 2 of the MD-2 gene. Similar to MD-2, MD-2s is glycosylated and secreted. MD-2s also interacted with LPS and TLR4, but failed to mediate LPS-induced NF-kappaB activation and IL-8 production. We show that MD-2s is upregulated upon IFN-gamma, IL-6, and TLR4 stimulation and negatively regulates LPS-mediated TLR4 signaling. Furthermore, MD-2s competitively inhibited binding of MD-2 to TLR4. Our study pinpoints a mechanism that may be used to regulate TLR4 activation at the onset of signaling and identifies MD-2s as a potential therapeutic candidate to treat human diseases characterized by an overly exuberant or chronic immune response to LPS.
J Immunol. 2010 Jun 1;184(11):6359-66. Epub 2010 Apr 30.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/33113