Testosterone suppresses protective responses of the liver to blood-stage malaria.
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-mum-diameter fluorescent polystyrol particles. However, testosterone delays malaria-induced closing of the liver, but not the spleen. Coincidently, testosterone causes an approximately 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.
Krücken
Jürgen
J
Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Dkhil
Mohamed A
MA
Braun
Juliane V
JV
Schroetel
Regina M U
RM
El-Khadragy
Manal
M
Carmeliet
Peter
P
Mossmann
Horst
H
Wunderlich
Frank
F
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000276:immunology*; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000276:immunology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000276:immunology; D015238:Sulfotransferases / Q000235:genetics / Q000502:physiology; D013739:Testosterone / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D017395:Plasminogen Activator Inhibitor 1; D013739:Testosterone; D015238:Sulfotransferases; C028152:alcohol sulfotransferase