Journal
INTERNATIONAL IMMUNOLOGY
Volume 25, Issue 1, Pages 45-52Publisher
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxs084
Keywords
human TLR4; polymorphism; MPL
Categories
Funding
- Japanese-Korean Cooperative Programme on Basic Medical Research (JST)
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) for Program of Japan Initiative for Global Research Network on Infectious Diseases [10005010]
- Global COE Program 'Center of Education and Research for the Advanced Genome-Based Medicine', MEXT, Japan [F06]
- [20390140]
- [20659074]
- [21117002]
- Grants-in-Aid for Scientific Research [24117706, 21117007] Funding Source: KAKEN
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Disease-associated TLR4 polymorphisms affect ligand-induced dimerization.A cell surface heterodimer Toll-like receptor 4 (TLR4)/MD-2 senses lipopolysaccharide (LPS), a principal membrane component of Gram-negative bacteria. LPS binds to MD-2 and induces dimerization of TLR4/MD-2. Dimerized TLR4 activates downstream signaling. TLR4 polymorphism replacing Asp299 with Gly and Thr399 with Ile (D299G/T399I) causes LPS hyporesponsiveness, and is associated with a variety of infectious and noninfectious diseases. However, a molecular mechanism underlying the LPS hyporesponsiveness remains controversial. We here asked whether the TLR4 polymorphism influenced cell surface expression of TLR4/MD-2, ligand-dependent TLR4/MD-2 dimerization or TLR4/MD-2 responses to a weak agonist monophosphoryl lipid A (MPL). A newly established anti-TLR4 mAb detected D299G/T399I TLR4/MD-2 on Ba/F3 cells, whereas a previous anti-TLR4 mAb did will this fit on the line above?, suggesting that the D299G/T399I polymorphism caused a conformational change in TLR4. Hyporesponsiveness of D299G/T399I TLR4/MD-2 was much more apparent when cells were stimulated with MPL than with lipid A. MPL-dependent TLR4/MD-2 dimerization was impaired by the D299G/T399I polymorphism. The D299G/T399I polymorphism did not alter LPS-binding to soluble TLR4/MD-2, but impaired its dimerization. These results suggest that the D299G/T399I TLR4 polymorphism impairs TLR4/MD-2 responses by altering ligand-dependent dimerization.
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