Regulatory Roles for CD14 and Phosphatidylinositol in the Signaling via Toll-like Receptor 4-MD-2

Akashi, Shigeo; Ogata, Hirotaka; Kirikae, Fumiko; Kirikae, Teruo; Kawasaki, Kiyoshi; Nishijima, Masahiro; Shimazu, Rintaro; Nagai, Yoshinori; Fukudome, Kenji; Kimoto, Masao; Miyake, Kensuke

doi:10.1006/bbrc.2000.2089

Cited by 130 publications

(82 citation statements)

References 36 publications

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“…These results suggest that CD14 is involved in the signaling events induced by flavolipin. Such an effect of CD14 has also been reported in the case of LPS-induced NF-B activation (33) (Fig. 3, B and C).…”

Section: Expression Of Cd14 Enhances Flavolipin Responsivenesssupporting

confidence: 81%

Toll-Like Receptor 4-MD-2 Complex Mediates the Signal Transduction Induced by Flavolipin, an Amino Acid-Containing Lipid Unique toFlavobacterium meningosepticum

Gomi

Kawasaki

Kawai

et al. 2002

The Journal of Immunology

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Flavolipin, an amino acid-containing lipid isolated from Flavobacterium meningosepticum, induces many immune responses. It has been shown that flavolipin does not induce an immune response of macrophages derived from C3H/HeJ mice, which possess a point mutation in Toll-like receptor 4 (TLR4). To determine whether TLR4 or the molecular complex of TLR4 and TLR4 association molecule MD-2 mediates the flavolipin signal, flavolipin responsiveness was examined by measuring NF-κB activation in Ba/F3 cells and Ba/F3 transfectants expressing TLR4 or both TLR4 and MD-2. Flavolipin-induced NF-κB activation was detected in the cells expressing both TLR4 and MD-2, but not in the other cells. Expression of CD14 in the transfectant expressing both TLR4 and MD-2 increased the sensitivity to flavolipin. Furthermore, flavolipin stereoisomers were chemically synthesized, and their abilities to induce NF-κB activation were examined. (R)-Flavolipin, in which the configuration of the lipid moiety is R, induced NF-κB activation via the TLR4-MD-2 complex, but (S)-flavolipin did not. In this study, we demonstrated the involvement of TLR4-MD-2 and CD14 in flavolipin signaling and the importance of the (R)-configuration of the flavolipin lipid moiety for the induction of an immune response via TLR4-MD-2.

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Section: Expression Of Cd14 Enhances Flavolipin Responsivenesssupporting

confidence: 81%

Toll-Like Receptor 4-MD-2 Complex Mediates the Signal Transduction Induced by Flavolipin, an Amino Acid-Containing Lipid Unique toFlavobacterium meningosepticum

Gomi

Kawasaki

Kawai

et al. 2002

The Journal of Immunology

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“…Finally, the hypothesis that this region is a primary ligandbinding region suggests other roles for the remaining, more highly conserved portions of TLR4's extracellular domain. The functions of these other two extracellular regions may be explained as sites for coreceptor interaction and endogenous ligand interaction, based on experimental evidence for the importance of such coreceptors as MD-2 and CD14 (30,31) and endogenous ligands such as hsp60, hyaluronan oligosaccharides, and ␤-defensin 2 (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Haplotype variation in bovine Toll-like receptor 4 and computational prediction of a positively selected ligand-binding domain

White

Taylor

Abbey

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Toll-like receptor 4 (TLR4) is a cell-surface receptor that activates innate and adaptive immune responses. Because it recognizes a broad class of pathogen-associated molecular patterns presented by lipopolysaccharides and lipoteichoic acid, TLR4 is a candidate gene for resistance to a large number of diseases. In particular, mouse models suggest TLR4 as a candidate gene for resistance to major agents in bovine respiratory disease and Johne's disease. The coding sequence of bovine TLR4 is divided into three exons, with intron͞exon boundaries and intron sizes similar to those of human TLR4 transcript variant 1. We amplified each exon in 40 individuals from 11 breeds and screened the sequence for singlenucleotide polymorphisms (SNPs). We identified 32 SNPs, 28 of which are in the coding sequence, for an average of one SNP per 90 bp of coding sequence. Eight SNPs were nonsynonymous and potentially alter specificity of pathogen recognition or efficiency of signaling. To evaluate the functional importance of these SNPs, we used codon-substitution models to detect diversifying selection in an extracellular region that may physically interact with ligands. One nonsynonymous SNP is located within this region, and other substitutions are in adjacent regions that may interact with coreceptor molecules. The 32 SNPs were found in 20 haplotypes that can be assigned to geographic ranges of origin. Haplotype-tagging SNP analysis indicated that 12 SNPs need to be genotyped to distinguish these 20 haplotypes. These data provide a basic understanding of bovine TLR4 sequence variation and supply haplotype markers for disease association studies.

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“…MD-2 is a protein that appears to be required for TLR-4 function. It is secreted from macrophages (40) and is believed to be important in mediating LPS-induced signaling events (67,68). The results presented by Yang et al (43) suggest that MD-2 can contribute to the LPS-induced activation of the MAPKs in a heterologous system.…”

Section: Discussionmentioning

confidence: 99%

A Differential Role for the Mitogen-activated Protein Kinases in Lipopolysaccharide Signaling

Watters¹,

Sommer²,

Pfeiffer³

et al. 2002

Journal of Biological Chemistry

116

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Endotoxin (lipopolysaccharide, LPS) is a component of the outer membrane of Gram-negative bacteria and promotes the activation of macrophages and microglia. Although these cells are highly LPS-responsive, they serve unique tissue-specific functions and exhibit different LPS sensitivities. Accordingly, it was of interest to evaluate whether these biological differences reside in variations within LPS signaling pathways between these two cell types. Because the mitogen-activated protein kinases ERK-1 and ERK-2 have been implicated in the control of many immune responses, we tested the concept that they are a key indicator for differences in cellular LPS sensitivity. We observed that murine RAW 264.7 macrophages and murine BV-2 microglial cells both respond to LPS by exhibiting increased IB␣ degradation, enhanced NF-B DNA binding activity, and elevated nitric oxide and interleukin-1␤ production. Although LPS potently stimulates ERK activation in RAW 264.7 macrophages, it does not activate ERK-1/-2 in BV-2 microglia. Moreover, antagonism of the MEK/ERK pathway potentiates LPS-stimulated nitric oxide production, suggesting that LPS-stimulated ERK activation can exert inhibitory effects in macrophage-like cells. These data support the idea that ERK activation is not a required function of LPS-mediated signaling events and illustrate that alternative/additional pathways for LPS action exist in these cell types.

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Regulatory Roles for CD14 and Phosphatidylinositol in the Signaling via Toll-like Receptor 4-MD-2

Cited by 130 publications

References 36 publications

Toll-Like Receptor 4-MD-2 Complex Mediates the Signal Transduction Induced by Flavolipin, an Amino Acid-Containing Lipid Unique toFlavobacterium meningosepticum

Toll-Like Receptor 4-MD-2 Complex Mediates the Signal Transduction Induced by Flavolipin, an Amino Acid-Containing Lipid Unique toFlavobacterium meningosepticum

Haplotype variation in bovine Toll-like receptor 4 and computational prediction of a positively selected ligand-binding domain

A Differential Role for the Mitogen-activated Protein Kinases in Lipopolysaccharide Signaling

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