Identification of a novel human MD-2 splice variant that negatively regulates Lipopolysaccharide-induced TLR4 signaling
Interdisciplinary Graduate Program
Department of Medicine, Division of Infectious Diseases and Immunology
Medical Subject Headings
Cell 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 | Life Sciences | Medicine and Health Sciences
Myeloid 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.
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Citation: J Immunol. 2010 Jun 1;184(11):6359-66. Epub 2010 Apr 30.