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Hepatocyte Nuclear Factor 1α Controls the Expression of Terminal Complement Genes

The terminal components of the complement system contribute to host defense by forming the multiprotein membrane attack complex (MAC) which is responsible for cell lysis and several noncytotoxic effects. Most of the complement proteins are synthesized in the liver, but the mechanisms controlling the...

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Autores principales: Pontoglio, Marco, Pausa, Mario, Doyen, Antonia, Viollet, Benoit, Yaniv, Moshe, Tedesco, Francesco
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2001
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193531/
https://www.ncbi.nlm.nih.gov/pubmed/11733582
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author Pontoglio, Marco
Pausa, Mario
Doyen, Antonia
Viollet, Benoit
Yaniv, Moshe
Tedesco, Francesco
author_facet Pontoglio, Marco
Pausa, Mario
Doyen, Antonia
Viollet, Benoit
Yaniv, Moshe
Tedesco, Francesco
author_sort Pontoglio, Marco
collection PubMed
description The terminal components of the complement system contribute to host defense by forming the multiprotein membrane attack complex (MAC) which is responsible for cell lysis and several noncytotoxic effects. Most of the complement proteins are synthesized in the liver, but the mechanisms controlling their tissue-specific expression have not been elucidated. In this study we show that mice lacking the hepatic transcription factor hepatocyte nuclear factor 1α (HNF1α) fail to transcribe C5 and C8A complement genes. In addition, mRNAs encoding for several other terminal complement components or subunits are expressed at lower levels, including C8β, C8γ, and C9. We next used a reconstitution assay involving human sera with selective complement deficiencies to assess mouse complement activity. Sera from HNF1α-deficient mice showed negligible hemolytic activity of both C5 and C8α-γ subunits. The activity of C8β was severely affected despite only a 50% reduction in C8β mRNA levels in the liver. This is reminiscent of C8α-γ–deficient patients who accumulate extremely low levels of the C8β subunit. Our results demonstrate that HNF1α plays a key role in the expression of C5 and C8A genes, two terminal complement component genes that are essential for the assembly of MAC as a result of complement activation.
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spelling pubmed-21935312008-04-14 Hepatocyte Nuclear Factor 1α Controls the Expression of Terminal Complement Genes Pontoglio, Marco Pausa, Mario Doyen, Antonia Viollet, Benoit Yaniv, Moshe Tedesco, Francesco J Exp Med Original Article The terminal components of the complement system contribute to host defense by forming the multiprotein membrane attack complex (MAC) which is responsible for cell lysis and several noncytotoxic effects. Most of the complement proteins are synthesized in the liver, but the mechanisms controlling their tissue-specific expression have not been elucidated. In this study we show that mice lacking the hepatic transcription factor hepatocyte nuclear factor 1α (HNF1α) fail to transcribe C5 and C8A complement genes. In addition, mRNAs encoding for several other terminal complement components or subunits are expressed at lower levels, including C8β, C8γ, and C9. We next used a reconstitution assay involving human sera with selective complement deficiencies to assess mouse complement activity. Sera from HNF1α-deficient mice showed negligible hemolytic activity of both C5 and C8α-γ subunits. The activity of C8β was severely affected despite only a 50% reduction in C8β mRNA levels in the liver. This is reminiscent of C8α-γ–deficient patients who accumulate extremely low levels of the C8β subunit. Our results demonstrate that HNF1α plays a key role in the expression of C5 and C8A genes, two terminal complement component genes that are essential for the assembly of MAC as a result of complement activation. The Rockefeller University Press 2001-12-03 /pmc/articles/PMC2193531/ /pubmed/11733582 Text en Copyright © 2001, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Original Article
Pontoglio, Marco
Pausa, Mario
Doyen, Antonia
Viollet, Benoit
Yaniv, Moshe
Tedesco, Francesco
Hepatocyte Nuclear Factor 1α Controls the Expression of Terminal Complement Genes
title Hepatocyte Nuclear Factor 1α Controls the Expression of Terminal Complement Genes
title_full Hepatocyte Nuclear Factor 1α Controls the Expression of Terminal Complement Genes
title_fullStr Hepatocyte Nuclear Factor 1α Controls the Expression of Terminal Complement Genes
title_full_unstemmed Hepatocyte Nuclear Factor 1α Controls the Expression of Terminal Complement Genes
title_short Hepatocyte Nuclear Factor 1α Controls the Expression of Terminal Complement Genes
title_sort hepatocyte nuclear factor 1α controls the expression of terminal complement genes
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193531/
https://www.ncbi.nlm.nih.gov/pubmed/11733582
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