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Laboratory Investigation (2006) 86, 873888
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www.laboratoryinvestigation.orgMatrix metalloproteinases, tissue inhibitors
of MMPs and TACE in experimental
cerebral malariaPhilippe E Van den Steen1, Ilse Van Aelst1, Sofie Starckx1, Klaus Maskos2,
Ghislain Opdenakker1 and Axel Pagenstecher31Laboratory of Immunobiology, Rega Institute, University of Leuven, Leuven, Belgium; 2Abteilung
Strukturforschung, Max-Planck-Institut fur Biochemie, Martinsried, Germany and3Department of
Neuropathology, University of Marburg, Marburg, GermanyCerebral malaria (CM) is a life-threatening disorder and a major medical problem in developing countries. It is
caused by the sequestration of malaria-infected erythrocytes onto brain endothelia, followed by bloodbrain
barrier (BBB) damage and neurological deficit. In the present study, matrix metalloproteinases (MMPs) were
analysed in a mouse model of CM with Plasmodium berghei ANKA. Increased numbers of gelatinase B (MMP-9)positive cells, which were also CD11b , were detected in the brain. In addition, activation of gelatinase B
occurred in CM brains, and not in brains of mice with non-CM. However, selective genetic knockout of
gelatinase B did not alter the clinical evolution of experimental CM. To study other protease balances, the
mRNA expression levels of nine matrix metalloproteinases (MMPs), five membrane-type MMPs, TNF-a
converting enzyme (TACE) and the four tissue inhibitors of metalloproteinases (TIMPs) were analysed during
CM in different organs. Significant alterations in expression were observed, including increases of the mRNAs
of MMP-3, -8, -13 and -14 in the spleen, MMP-8, -12, -13 and -14 in the liver and MMP-8 and -13 in the brain. Net
gelatinolytic activity, independent of gelatinase B and inhibitable with EDTA, was detected in situ in the
endothelia of blood vessels in CM brains, but not in brains of mice with non-CM, suggesting that
metalloproteases, different from gelatinase B, are active in the BBB environment in CM. The increase in MMP
expression in the brain was significantly less pronounced after infection of C57Bl/6 mice with the noncerebral
strain P. berghei NK65, but it was similar in CM-susceptible C57Bl/6 and CM-resistant Balb/C mice upon
infection with P. berghei ANKA. Furthermore, in comparison with C57Bl/6 mice, a larger increase in TIMP-1 and
a marked, 430-fold induction in MMP-3 were found in the brains of Balb/C mice, suggesting possible protective
roles for TIMP-1 and MMP-3.Laboratory Investigation (2006) 86, 873888. doi:10.1038/labinvest.3700454; published online 24 July 2006Keywords: cerebral...