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*
Institut National de la Santé et de la Recherche Médicale U433, Faculté de Médecine R. Laënnec, Lyon, France; and
Department of Neuroscience, Hospital del Salvador, Faculty of Medicine, University of Chile, Santiago, Chile
Activation of T lymphocytes by human pathogens is a key step in the
development of immune-mediated neurologic diseases. Because of their
ability to invade the CNS and their increased secretion of
proinflammatory cytokines, activated CD4+ T cells are
thought to play a crucial role in pathogenesis. In the present study,
we examined the expression of inflammatory mediators the
cytokine-induced metalloproteinases (MMP-2, -3, and -9) and their
endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMP-1,
-2, and -3), in human astrocytes in response to activated T cells. We
used a model system of CD4+ T lymphocytes activated by
persistent viral infection (human T lymphotropic virus, HTLV-I) in
transient contact with human astrocytes. Interaction with T cells
resulted in increased production of MMP-3 and active MMP-9 in
astrocytes despite increased expression of endogenous inhibitors,
TIMP-1 and TIMP-3. These data suggest perturbation of the MMP/TIMP
balance. These changes in MMP and TIMP expression were mediated, in
part, by soluble factors (presumably cytokines) secreted by activated T
cells. Integrin-mediated cell adhesion is also involved in the change
in MMP level, since blockade of integrin subunits (
1,
3,
5, and ß1) on T cells
resulted in less astrocytic MMP-9-induced expression. Interestingly, in
CNS tissues from neurological HTLV-I-infected patients, MMP-9 was
detected in neural cells within the perivascular space, which is
infiltrated by mononuclear cells. Altogether, these data emphasize the
importance of the MMP-TIMP axis in the complex interaction between the
CNS and invading immune cells in the context of virally mediated T cell
activation.
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