Endotoxin recognition and signal transduction by the TLR4/MD2-complex

Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, LRB, Room 308, 364 Plantation Street, Worcester, MA 01605, USA.
Microbes and Infection (Impact Factor: 2.86). 01/2005; 6(15):1361-7. DOI: 10.1016/j.micinf.2004.08.015
Source: PubMed


Bacterial lipopolysaccharides are recognized in mammals by a receptor complex composed of CD14, Toll-like receptor (TLR)-4 and MD-2. Transduction of signaling is achieved following the recruitment of a combination of four Toll-interleukin-1 resistance (TIR)-domain-containing adapter molecules, which provide a structural platform enabling the recruitment and activation of downstream effectors essential for pathway-specific transcription factor activation and inflammatory gene expression.

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    • "LPS binding protein (LBP), CD14, and MD-2 are all expressed in the eye and are integral components of the TLR4 recognition system [24], [25]. LBP binds to LPS and transfers the PAMPs onto CD14 [26]. MD-2 is a co-receptor that binds to TLR4 and to LPS making it essential for response [27]. "
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    ABSTRACT: Free-living amoebae of the Acanthamoeba species are the causative agent of Acanthamoeba keratitis (AK), a sight-threatening corneal infection that causes severe pain and a characteristic ring-shaped corneal infiltrate. Innate immune responses play an important role in resistance against AK. The aim of this study is to determine if Toll-like receptors (TLRs) on corneal epithelial cells are activated by Acanthamoeba, leading to initiation of inflammatory responses in the cornea. Human corneal epithelial (HCE) cells constitutively expressed TLR1, TLR2, TLR3, TLR4, and TLR9 mRNA, and A. castellanii upregulated TLR4 transcription. Expression of TLR1, TLR2, TLR3, and TLR9 was unchanged when HCE cells were exposed to A. castellanii. IL-8 mRNA expression was upregulated in HCE cells exposed to A. castellanii. A. castellanii and lipopolysaccharide (LPS) induced significant IL-8 production by HCE cells as measured by ELISA. The percentage of total cells positive for TLR4 was higher in A. castellanii stimulated HCE cells compared to unstimulated HCE cells. A. castellanii induced upregulation of IL-8 in TLR4 expressing human embryonic kidney (HEK)-293 cells, but not TLR3 expressing HEK-293 cells. TLR4 neutralizing antibody inhibited A. castellanii-induced IL-8 by HCE and HEK-293 cells. Clinical strains but not soil strains of Acanthamoeba activated TLR4 expression in Chinese hamster corneas in vivo and in vitro. Clinical isolates but not soil isolates of Acanthamoeba induced significant (P< 0.05) CXCL2 production in Chinese hamster corneas 3 and 7 days after infection, which coincided with increased inflammatory cells in the corneas. Results suggest that pathogenic species of Acanthamoeba activate TLR4 and induce production of CXCL2 in the Chinese hamster model of AK. TLR4 may be a potential target in the development of novel treatment strategies in Acanthamoeba and other microbial infections that activate TLR4 in corneal cells.
    PLoS ONE 03/2014; 9(3):e92375. DOI:10.1371/journal.pone.0092375 · 3.23 Impact Factor
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    • "Then, LPS-LBP complex binds to the CD14 protein, which is necessary for the activation of TLR4. CD14, MD-2, and TLR4 as a whole make up the cellular LPS specific receptor [8, 9]. After activation by endotoxin, TLR4 transduces its inflammatory signal through complex intracellular pathways, leading to activation of transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), c-Jun N-terminal kinase (JNK), and protein kinases p38 or inducing cell apoptosis [10, 11]. "
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    ABSTRACT: The present study was designed to examine the effect of intracerebroventricular (icv) administration of antilipopolysaccharide (LPS) antibody and blockade of Toll-like receptor 4 (TLR4) during immune stress induced by intravenous (iv) LPS injection on the gonadotropin-releasing hormone/luteinizing hormone (GnRH/LH) secretion in anestrous ewes. Injection of anti-LPS antibody and TLR4 blockade significantly (P < 0.01) reduced the LPS dependent lowering amount of GnRH mRNA in the median eminence (ME). Moreover, blockade of TLR4 caused restoration of LH- β transcription in the anterior pituitary decreased by the immune stress. However, there was no effect of this treatment on reduced LH release. The results of our study showed that the blockade of TLR4 receptor in the hypothalamus is not sufficient to unblock the release of LH suppressed by the immune/inflammatory challenges. This suggests that during inflammation the LH secretion could be inhibited directly at the pituitary level by peripheral factors such as proinflammatory cytokines and circulating endotoxin as well.
    Mediators of Inflammation 02/2014; 2014(3):867170. DOI:10.1155/2014/867170 · 3.24 Impact Factor
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    • "CD16, the low affinity Fcγ receptor III for IgG (FcγRIII) exists as a polypeptide-anchored form (FcγRIIIA, or CD16-A) in human natural killer cells and monocyte/macrophages, and as a GPI-anchored form in human neutrophils (FcγRIIIB or CD16-B) [29]. CD14 is a component of the innate immune system that along with the Toll-like receptor 4 and MD-2, acts as a co-receptor for the detection of bacterial lipopolysaccharide and also exists in two forms: either anchored into the membrane by a GPI tail (mCD14), or present in a soluble form (sCD14) [30]. Reduced CD16 expression is likely to contribute to the impaired clearance of immune complexes [31]. "
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    ABSTRACT: Mutations in PMM2 impair phosphomannomutase-2 activity and cause the most frequent congenital disorder of glycosylation, PMM2-CDG. Mannose-1-phosphate, that is deficient in this disorder, is also implicated in the biosynthesis of glycosylphosphatidyl inositol (GPI) anchors. To evaluate whether GPI-anchor and GPI-anchored proteins are defective in PMM2-CDG patients.Methods The expression of GPI-anchor and seven GPI-anchored proteins was evaluated by flow cytometry in different cell types from twelve PMM2-CDG patients. Additionally, neutrophil CD16 and plasma hepatic proteins were studied by Western blot. Transferrin glycoforms were evaluated by HPLC. Patients and controls had similar surface expression of GPI-anchor and most GPI-anchored proteins. Nevertheless, patients displayed a significantly diminished binding of two anti-CD16 antibodies (3G8 and KD1) to neutrophils and also of anti-CD14 (61D3) to monocytes. Interestingly, CD16 immunostaining and asialotransferrin levels significantly correlated with patients' age. Analysis by flow cytometry of CD14 with MPhiP9, and CD16 expression in neutrophils by Western blot using H-80 ruled out deficiencies of these antigens. PMM2 mutations do not impair GPI-anchor or GPI-anchored protein expression. However, the glycosylation anomalies caused by PMM2 mutations might affect the immunoreactivity of monoclonal antibodies and lead to incorrect conclusions about the expression of different proteins, including GPI-anchored proteins. Neutrophils and monocytes are sensitive to PMM2 mutations, leading to abnormal glycosylation in immune receptors, which might potentially affect their affinity to their ligands, and contribute to infection. This study also confirms less severe hypoglycosylation defects in older PMM2-CDG patients.
    Orphanet Journal of Rare Diseases 10/2013; 8(1):170. DOI:10.1186/1750-1172-8-170 · 3.36 Impact Factor
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