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Molecular and Cellular Biology, March 2001, p. 1621-1632, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1621-1632.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Essential Role of STAT3 in the Control of the Acute-Phase Response as Revealed by Inducible Gene Activation in the Liver

Tonino Alonzi,1,dagger Diego Maritano,1 Barbara Gorgoni,1 Gabriella Rizzuto,2 Claude Libert,2,Dagger and Valeria Poli1,*

School of Life Sciences, Wellcome Trust Biocenter, University of Dundee, Dundee DD1 5EH, Scotland,1 and Istituto Ricerche di Biologia Molecolare Angeletti, Pomezia, Italy2

Received 17 July 2000/Returned for modification 3 October 2000/Accepted 8 December 2000

We generated mice carrying a STAT3 allele amenable to Cre-mediated deletion and intercrossed them with Mx-Cre transgenic mice, in which the expression of Cre recombinase can be induced by type I interferon. Interferon-induced deletion of STAT3 occurred very efficiently (more than 90%) in the liver and slightly less efficiently (about 70%) in the bone marrow. Analysis of the induction of liver acute-phase genes in response to bacterial lipopolysaccharide unequivocally identifies STAT3 as a fundamental mediator of their induction. The different degrees of defectiveness displayed by the various genes allowed us to differentiate them into three separate groups according to their degree of dependence on STAT3. Induction was totally defective for group I genes, defective at 24 h but almost normal at earlier time points for group II genes, and only slightly defective for group III genes. This division was in good agreement with the known structures of the respective promoters. We also found that the overall induction of the transcription factors C/EBPbeta and -delta was only minimally defective in the absence of STAT3. Finally, even though corticosterone levels and action were found to be normal in the conditional-mutant mice, production of both proinflammatory and antiinflammatory cytokines was increased and prolonged, probably as a result of STAT3 deletion in macrophages.

* Corresponding author. Mailing address: School of Life Sciences, Wellcome Trust Biocenter, University of Dundee, Dow St., Dundee DD1 5EH, Scotland. Phone: 44-1382-345787. Fax: 44-1382-345893. E-mail: v.poli{at}dundee.ac.uk.

dagger Present address: Laboratory of Gene Expression, I. R. C. C. S. "L. Spallanzani," Rome, Italy.

Dagger Present address: Department of Molecular Biology, University of Ghent, 9000 Ghent, Belgium.

Molecular and Cellular Biology, March 2001, p. 1621-1632, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1621-1632.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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