The Journal of Experimental Medicine
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Published 3 December 2001. doi:10.1084/jem.194.11.1683
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© Rockefeller University Press, 0022-1007/2001/12/1683/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 11, December 3, 2001 1683-1690

Original Article

Hepatocyte Nuclear Factor 1{alpha} Controls the Expression of Terminal Complement Genes

Marco Pontoglio1, Mario Pausa2, Antonia Doyen1, Benoit Viollet1, Moshe Yaniv1 and Francesco Tedesco3

1 Unité des Virus Oncogènes, Centre National de la Recherche Scientifique URA 1644, Département de Biotechnologie, Institut Pasteur, 75724 Paris cedex 15, France
2 Istituto Diricovero E Cura A Carattere Scientifico (IRCCS), Burlo Garofolo, Trieste, Italy via dell'Istria N°1 Trieste 34100, Italy
3 Department of Physiology and Pathology, University of Trieste, via Fleming 22 34100 Trieste, Italy

Address correspondence to M. Pontoglio, Unité des Virus Oncogènes, Centre National de la Recherche Scientifique URA 1644, Département de Biotechnologie, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris cedex 15, France. Phone: 33-1-45688514; Fax: 33-1-40613033; E-mail: marcop{at}pasteur.fr

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 1{alpha} (HNF1{alpha}) 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 C8ß, C8{gamma}, and C9. We next used a reconstitution assay involving human sera with selective complement deficiencies to assess mouse complement activity. Sera from HNF1{alpha}-deficient mice showed negligible hemolytic activity of both C5 and C8{alpha}-{gamma} subunits. The activity of C8ß was severely affected despite only a 50% reduction in C8ß mRNA levels in the liver. This is reminiscent of C8{alpha}-{gamma}–deficient patients who accumulate extremely low levels of the C8ß subunit.

Our results demonstrate that HNF1{alpha} 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.

Key Words: HNF1{alpha} • complement • C5 • C8 {alpha} • transcription


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