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Hum Immunol ; 69(12): 861-6, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18822328


Chronic hepatitis C (HCV) represents one of the most common chronic infections worldwide and is a major indication for liver transplantation. Liver inflammation is the main predictor of advanced fibrosis in HCV. Inflammatory cells are recruited to the liver by chemokines. Recently, a novel class of chemokine receptors has been characterized that lack signaling functions and are termed scavenger receptors. We determine here whether genetic variations of the scavenger receptor D6 contribute to the grade of liver inflammation in HCV. Four haplotype tagging single nucleotide polymorphisms (SNPs) were identified from HapMap that cover the genetic information of D6 (CCBP2). Among these SNPs, rs4683336 was associated with liver inflammation in qualitative (p = 0.003) and quantitative (p = 0.0086) genotype analysis. This association was confirmed in an independent cohort of HCV-infected patients (p = 0.006 for qualitative and p = 0.0046 for quantitative analysis, respectively). Furthermore, the haplotype that is tagged by marker rs4683336 was significantly correlated with liver inflammation when compared with the most common D6 haplotype (p = 0.014). The importance of genetic variations in D6 was supported through the demonstration of an association of D6 mRNA expression with histologic inflammation in liver biopsies and a considerable range of D6 mRNA expression in isolated human hepatocytes. In conclusion, we demonstrate that variations in a chemokine scavenging receptor are significantly correlated with clinical inflammatory phenotypes such as HCV infection.

Hepacivirus/imunologia , Hepatite C Crônica/genética , Hepatite C Crônica/imunologia , Hepatócitos/metabolismo , RNA Mensageiro/análise , Receptores de Quimiocinas/imunologia , Receptores Depuradores Classe D/genética , Receptores Depuradores Classe D/imunologia , Adulto , Biomarcadores/análise , Células Cultivadas , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/fisiopatologia , Hepatócitos/imunologia , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptores de Quimiocinas/genética
Amino Acids ; 25(3-4): 283-92, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14661091


Our present knowledge on chemically modified proteins and their receptor systems is originated from a proposal by Goldstein and Brown in 1979 for the receptor for acetylated LDL which is involved in foam cell formation, one of critical steps in atherogenesis. Subsequent extensive studies using oxidized LDL (OxLDL) as a representative ligand disclosed at least 11 different scavenger receptors which are collectively categorized as "scavenger receptor family". Advanced glycation endproducts (AGE) and their receptor systems have been studied independently until recent findings that AGE-proteins are also recognized as active ligands by scavenger receptors including class A scavenger receptor (SR-A), class B scavenger receptors such as CD36 and SR-BI, type D scavenger receptor (LOX-1) and FEEL-1/FEEL-2. Three messages can be summarized from these experiments; (i) endocytic uptake of OxLDL and AGE-proteins by macrophages or macrophage-derived cells is mainly mediated by SR-A and CD36, which is an important step for foam cell formation in the early stage of atherosclerosis, (ii) selective uptake of cholesteryl esters of high density lipoprotein (HDL) mediated by SR-BI is inhibited by AGE-proteins, suggesting a potential pathological role of AGE in a HDL-mediated reverse cholesterol transport system, (iii) a novel scavenger receptor is involved in hepatic clearance of plasma OxLDL and AGE-proteins.

Proteínas/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores Imunológicos/metabolismo , Animais , Antígenos CD36 , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Ligantes , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Modelos Biológicos , Oxirredução , Proteínas/química , Receptores Imunológicos/classificação , Receptores Depuradores , Receptores Depuradores Classe A , Receptores Depuradores Classe B , Receptores Depuradores Classe D , Receptores Depuradores Classe E
J Endotoxin Res ; 7(5): 381-4, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11753207


This study was undertaken to identify the role of scavenger receptors in the catabolism of lipopolysaccharide (LPS) and lipoteichoic acid (LTA). LPS is mainly cleared from the blood by the liver. The Kupffer cells are primarily responsible for this clearance. Although several binding sites have been described for LPS and LTA, only CD14 is involved in LPS signalling. Scavenger receptor type A (SR-A) is expressed in the liver on endothelial cells and Kupffer cells, and macrosialin (class D scavenger receptor) is expressed on Kupffer cells. Fucoidin and poly-I are both good inhibitors of scavenger receptors. Fucoidin significantly reduced the serum clearance of [125I]-LPS and decreased liver uptake of [125I]-LPS by approximately 40%. Poly-I inhibited the binding of [125I]-LPS to isolated Kupffer and endothelial cells by 75%, while poly-A, a polyanionic substrate that does not block scavenger receptors, had no effect. LPS significantly inhibited the binding of acetylated LDL and oxidized LDL (two well-described scavenger receptor ligands) to isolated Kupffer and liver endothelial cells. OxLDL and acLDL did not affect the binding of LPS to these cells. We conclude that on both endothelial cells and Kupffer cells, LPS mainly binds to scavenger receptors, but SR-A and macrosialin contribute to a limited extent to the binding of LPS. Injection of LTA into C57Bl6 mice resulted in a maximal liver uptake of 20% of the injected dose. In the liver, 50% was bound by the Kupffer cells, 20% by parenchymal cells and 30% by liver endothelial cells. The contribution of SR-A to the plasma clearance of LTA was limited. A main component in the catabolism of LTA is the interaction of LTA with plasma lipoproteins, which limit the uptake of LTA by tissues and extend the plasma half-life of LTA.

Endotélio Vascular/metabolismo , Macrófagos do Fígado/metabolismo , Lipopolissacarídeos/farmacocinética , Fígado/irrigação sanguínea , Proteínas de Membrana , Receptores Imunológicos/metabolismo , Receptores de Lipoproteínas , Ácidos Teicoicos/farmacocinética , Animais , Radioisótopos do Iodo , Fígado/metabolismo , Camundongos , Poli A/farmacologia , Poli I/farmacologia , Polissacarídeos/farmacologia , Ratos , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/classificação , Receptores Depuradores , Salmonella/imunologia , Receptores Depuradores Classe A , Receptores Depuradores Classe B , Receptores Depuradores Classe D , Staphylococcus aureus/imunologia