T lymphocytes activated by persistent viral infection differentially modify the expression of metalloproteinases and their endogenous inhibitors, TIMPs, in human astrocytes: relevance to HTLV-I-induced neurological disease.
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 (alpha1, alpha3, alpha5, and beta1) 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.
Giraudon
P
P
Institut National de la Santé et de la Recherche Médicale U433, Faculté de Médecine R. Laënnec, Lyon, France. giraudon@lyon151.inserm.fr
Szymocha
R
R
Buart
S
S
Bernard
A
A
Cartier
L
L
Belin
M F
MF
Akaoka
H
H
D000328:Adult; D001253:Astrocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000201:enzymology / Q000473:pathology / Q000821:virology; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000276:immunology / Q000378:metabolism; D005260:Female; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D016023:Integrins / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D008875:Middle Aged; D015493:Paraparesis, Tropical Spastic / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D016326:Extracellular Matrix Proteins; D016023:Integrins; D007375:Interleukin-1; D008024:Ligands; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9