Identification of a novel human MD-2 splice variant that negatively regulates Lipopolysaccharide-induced TLR4 signaling
dc.contributor.author | Gray, Pearl | |
dc.contributor.author | Michelsen, Kathrin S. | |
dc.contributor.author | Sirois, Cherilyn M. | |
dc.contributor.author | Lowe, Emily | |
dc.contributor.author | Shimada, Kenichi | |
dc.contributor.author | Crother, Timothy R. | |
dc.contributor.author | Chen, Shuang | |
dc.contributor.author | Brikos, Constantinos | |
dc.contributor.author | Bulut, Yonca | |
dc.contributor.author | Latz, Eicke | |
dc.contributor.author | Underhill, David | |
dc.contributor.author | Arditi, Moshe | |
dc.date | 2022-08-11T08:08:53.000 | |
dc.date.accessioned | 2022-08-23T16:11:13Z | |
dc.date.available | 2022-08-23T16:11:13Z | |
dc.date.issued | 2010-06-01 | |
dc.date.submitted | 2010-09-15 | |
dc.identifier.citation | <p>J Immunol. 2010 Jun 1;184(11):6359-66. Epub 2010 Apr 30.</p> | |
dc.identifier.issn | 1550-6606 | |
dc.identifier.doi | 10.4049/jimmunol.0903543 | |
dc.identifier.pmid | 20435923 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/33113 | |
dc.description.abstract | 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. | |
dc.language.iso | en_US | |
dc.publisher | American Association of Immunologists | |
dc.relation | <p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=20435923&dopt=Abstract">Link to article in PubMed</a></p> | |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057206/ | |
dc.subject | 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 | |
dc.subject | Immunology and Infectious Disease | |
dc.subject | Life Sciences | |
dc.subject | Medicine and Health Sciences | |
dc.title | Identification of a novel human MD-2 splice variant that negatively regulates Lipopolysaccharide-induced TLR4 signaling | |
dc.type | Journal Article | |
dc.source.journaltitle | Journal of immunology (Baltimore, Md. : 1950) | |
dc.source.volume | 184 | |
dc.source.issue | 11 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/gsbs_sp/1656 | |
dc.identifier.contextkey | 1558856 | |
html.description.abstract | <p>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.</p> | |
dc.identifier.submissionpath | gsbs_sp/1656 | |
dc.contributor.department | Department of Medicine, Division of Infectious Diseases and Immunology | |
dc.contributor.student | Cherilyn M. Sirois |