Polymorphic variants of LIGHT (TNF superfamily-14) alter receptor avidity and bioavailability.

Abstract

The TNF superfamily member homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes (LIGHT) [TNF superfamily (SF)-14], is a key cytokine that activates T cells and dendritic cells and is implicated as a mediator of inflammatory, metabolic, and malignant diseases. LIGHT engages the lymphotoxin-beta receptor (LTbetaR) and HVEM (TNFRSF14), but is competitively limited in activating these receptors by soluble decoy receptor-3 (DcR3; TNFRSF6B). Two variants in the human LIGHT alter the protein at E214K (rs344560) in the receptor-binding domain and S32L (rs2291667) in the cytosolic domain; however, the functional impact of these polymorphisms is unknown. A neutralizing Ab failed to bind the LIGHT-214K variant, indicating this position as a part of the receptor-binding region. Relative to the predominant reference variant S32/E214, the other variants showed altered avidity with LTbetaR and less with HVEM. Heterotrimers of the LIGHT variants decreased binding avidity to DcR3 and minimized the inhibitory effect of DcR3 toward LTbetaR-induced activation of NF-kappaB. In patients with immune-mediated inflammatory diseases, such as rheumatoid arthritis, DcR3 protein levels were significantly elevated. Immunohistochemistry revealed synoviocytes as a significant source of DcR3 production, and DcR3 hyperexpression is controlled by posttranscriptional mechanisms. The increased potential for LTbetaR signaling, coupled with increased bioavailability due to lower DcR3 avidity, provides a mechanism of how polymorphic variants in LIGHT could contribute to the pathogenesis of inflammatory diseases.

• Authors: Timothy C Cheung, Ken Coppieters, Hideki Sanjo, Lisa M Oborne, Paula S Norris, Amy Coddington, Steven W Granger, Dirk Elewaut, Carl F Ware
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 3 Pg. 1949-58 (Aug 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20592286 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• NF-kappa B
• Receptors, Tumor Necrosis Factor, Member 14
• Receptors, Tumor Necrosis Factor, Member 6b
• TNFRSF6B protein, human
• Tumor Necrosis Factor Ligand Superfamily Member 14

Topics

• Amino Acid Sequence
• Biological Availability
• Coculture Techniques
• Genetic Variation (immunology)
• HeLa Cells
• Humans
• Inflammation Mediators (metabolism, physiology)
• Models, Immunological
• Molecular Sequence Data
• Mutagenesis, Site-Directed
• NF-kappa B (antagonists & inhibitors)
• Polymorphism, Single Nucleotide (immunology)
• Protein Binding (genetics, immunology)
• Receptors, Tumor Necrosis Factor, Member 14 (metabolism, physiology)
• Receptors, Tumor Necrosis Factor, Member 6b (physiology)
• Signal Transduction (genetics, immunology)
• Tumor Necrosis Factor Ligand Superfamily Member 14 (genetics, metabolism, physiology)