Title
Identification of a novel human MD-2 splice variant that negatively regulates Lipopolysaccharide-induced TLR4 signaling
Academic Program
Interdisciplinary Graduate Program
UMMS Affiliation
Department of Medicine, Division of Infectious Diseases and Immunology
Publication Date
2010-06-01
Document Type
Article
Disciplines
Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences
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.
DOI of Published Version
10.4049/jimmunol.0903543
Source
J Immunol. 2010 Jun 1;184(11):6359-66. Epub 2010 Apr 30.
Journal/Book/Conference Title
Journal of immunology (Baltimore, Md. : 1950)
Related Resources
PubMed ID
20435923
Repository Citation
Gray P, Michelsen KS, Sirois CM, Lowe E, Shimada K, Crother TR, Chen S, Brikos C, Bulut Y, Latz E, Underhill D, Arditi M. (2010). Identification of a novel human MD-2 splice variant that negatively regulates Lipopolysaccharide-induced TLR4 signaling. GSBS Student Publications. https://doi.org/10.4049/jimmunol.0903543. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1656