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Infection and Immunity, January 2005, p. 436-443, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.436-443.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Testosterone Suppresses Protective Responses of the Liver to Blood-Stage Malaria

Jürgen Krücken,1 Mohamed A. Dkhil,1 Juliane V. Braun,1 Regina M. U. Schroetel,1 Manal El-Khadragy,1 Peter Carmeliet,2 Horst Mossmann,3 and Frank Wunderlich1*

Division of Molecular Parasitology and Centre for Biological and Medical Research, Heinrich-Heine-University Düsseldorf, Düsseldorf,1 Max Planck Institute for Immunobiology, Freiburg, Germany,3 Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium2

Received 15 July 2004/ Returned for modification 6 September 2004/ Accepted 12 September 2004

Testosterone induces a lethal outcome in otherwise self-healing blood-stage malaria caused by Plasmodium chabaudi. Here, we examine possible testosterone effects on the antimalaria effectors spleen and liver in female C57BL/6 mice. Self-healing malaria activates gating mechanisms in the spleen and liver that lead to a dramatic reduction in trapping activity, as measured by quantifying the uptake of 3-µm-diameter fluorescent polystyrol particles. However, testosterone delays malaria-induced closing of the liver, but not the spleen. Coincidently, testosterone causes an ~3- to 28-fold depression of the mRNA levels of nine malaria-responsive genes, out of 299 genes tested, only in the liver and not in the spleen, as shown by cDNA arrays and Northern blotting. Among these are the genes encoding plasminogen activator inhibitor (PAI1) and hydroxysteroid sulfotransferase (STA2). STA2, which detoxifies bile acids, is suppressed 10-fold by malaria and an additional 28-fold by testosterone, suggesting a severe perturbation of bile acid metabolism. PAI1 is protective against malaria, since disruption of the PAI1 gene results in partial loss of the ability to control the course of P. chabaudi infections. Collectively, our data indicate that the liver rather than the spleen is a major target organ for testosterone-mediated suppression of resistance against blood-stage malaria.

* Corresponding author. Mailing address: Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany. Phone: (49) 211-811-4734. Fax: (49) 211-811-4734. E-mail: frank.wunderlich{at}uni-duesseldorf.de.

Editor: W. A. Petri, Jr.

Infection and Immunity, January 2005, p. 436-443, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.436-443.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Helmby, H. (2009). Gastrointestinal Nematode Infection Exacerbates Malaria-Induced Liver Pathology. J. Immunol. 182: 5663-5671 [Abstract] [Full Text]  
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