title: Matrix metalloproteinases, tissue inhibitors of MMPs and TACE in experimental cerebral malaria.
abstract: Cerebral 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 blood-brain 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-alpha 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, >30-fold induction in MMP-3 were found in the brains of Balb/C mice, suggesting possible protective roles for TIMP-1 and MMP-3.
authors.affiliation: Laboratory of Immunobiology, Rega Institute, University of Leuven, Leuven, Belgium. philippe.vandensteen@rega.kuleuven.ac.be
authors.forename: Philippe E
authors.initials: PE
authors.lastname: Van den Steen
authors.forename: Ilse
authors.initials: I
authors.lastname: Van Aelst
authors.forename: Sofie
authors.initials: S
authors.lastname: Starckx
authors.forename: Klaus
authors.initials: K
authors.lastname: Maskos
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.forename: Axel
authors.initials: A
authors.lastname: Pagenstecher
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D001921:Brain / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D004586:Electrophoresis; D015870:Gene Expression; D016779:Malaria, Cerebral / Q000188:drug therapy / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D010962:Plasmodium berghei; D013876:Thiophenes / Q000627:therapeutic use; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*
chemical_list: D039481:CD11b Antigen; D013876:Thiophenes; D019714:Tissue Inhibitor of Metalloproteinases; D010649:Phenylalanine; C080985:batimastat; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse