Journal Article

Human TLR4 polymorphism D299G/T399I alters TLR4/MD-2 conformation and response to a weak ligand monophosphoryl lipid A

Natsuko Yamakawa, Umeharu Ohto, Sachiko Akashi-Takamura, Koichiro Takahashi, Shin-Ichiroh Saitoh, Natsuko Tanimura, Takayoshi Suganami, Yoshihiro Ogawa, Takuma Shibata, Toshiyuki Shimizu and Kensuke Miyake

in International Immunology

Volume 25, issue 1, pages 45-52
Published in print January 2013 | ISSN: 0953-8178
Published online September 2012 | e-ISSN: 1460-2377 | DOI: http://dx.doi.org/10.1093/intimm/dxs084
Human TLR4 polymorphism D299G/T399I alters TLR4/MD-2 conformation and response to a weak ligand monophosphoryl lipid A

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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 not, 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.

Keywords: human TLR4; polymorphism; MPL

Journal Article.  4637 words.  Illustrated.

Subjects: Immunology ; Biological Sciences

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