Cytokines secreted by glial cells infected with HTLV-I modulate the expression of matrix metalloproteinases (MMPs) and their natural inhibitor (TIMPs): possible involvement in neurodegenerative processes

Giraudon, Pascale; Buart, Stéphanie; Bernard, Arlette; Mf, Belin

doi:10.1038/sj.mp.4000218

Cited by 40 publications

(32 citation statements)

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“…These results point to an in vivo link between the expression of certain MMPs, TIMPs, and cytokines consistent with the regulatory role of cytokines and in agreement with previously published data (19,21,48,49).…”

Section: Vol 75 2001 Mmp/timp Imbalance In Cdv-infected Brain Strucsupporting

confidence: 80%

“…Thus, the increased expression of MMP-2 and MMP-9, especially in the hippocampus, can be attributed to upregulation of IL-6 and TNF-␣, which have been described as the main actors in MMP modulation (19,26,54). TIMP-1 upregulation in the cortex, hippocampus, and hypothalamus could be due to synergistic activation of AP-1 (30) and polyoma enhancer activator 3 sites in the TIMP-1 promoter.…”

Section: Discussionmentioning

confidence: 99%

“…Since previous studies have indicated that the transcription of MMPs and TIMPs in neural cells is tightly regulated by cytokines (19,25,26), the expression of proinflammatory (interleukin 6 , tumor necrosis factor alpha [TNF-␣], and gamma interferon [IFN-␥]) and anti-inflammatory (IL-4 and IL-10) cytokines was studied. We show that the expression of MMP-2, MMP-9, membrane type 1-MMP (MT1-MMP), TIMP-1, and TIMP-3 was differentially upregulated in different cerebral regions.…”

mentioning

confidence: 99%

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Morbillivirus Infection of the Mouse Central Nervous System Induces Region-Specific Upregulation of MMPs and TIMPs Correlated to Inflammatory Cytokine Expression

Khuth

Akaoka

Pagenstecher

et al. 2001

J Virol

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Viral infection of the central nervous system (CNS) can result in perturbation of cell-to-cell communication involving the extracellular matrix (ECM). ECM integrity is maintained by a dynamic balance between the synthesis and proteolysis of its components, mainly as a result of the action of matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). An MMP/TIMP imbalance may be critical in triggering neurological disorders, in particular in virally induced neural disorders. In the present study, a mouse model of brain infection using a neurotropic strain of canine distemper virus (CDV) was used to study the effect of CNS infection on the MMP/TIMP balance and cytokine expression. CDV replicates almost exclusively in neurons and has a unique pattern of expression (cortex, hypothalamus, monoaminergic nuclei, hippocampus, and spinal cord). Here we show that although several mouse brain structures were infected, they exhibited a differential pattern in terms of MMP, TIMP, and cytokine expression, exemplified by (i) a large increase in pro-MMP9 levels, in particular in the hippocampus, which occurred mainly in neurons and was associated with in situ gelatinolytic activity, (ii) specific and significant upregulation of MT1-MMP mRNA expression in the cortex and hypothalamus, (iii) an MMP/TIMP imbalance, suggested by the upregulation of TIMP-1 mRNA in the cortex, hippocampus, and hypothalamus and of TIMP-3 mRNA in the cortex, and (iv) a concomitant region-specific large increase in expression of Th1-like cytokines, such as gamma interferon, tumor necrosis factor alpha, and interleukin 6 (IL-6), contrasting with weaker induction of Th2-like cytokines, such as IL-4 and IL-10. These data indicate that an MMP/TIMP imbalance in specific brain structures, which is tightly associated with a local inflammatory process as shown by the presence of immune infiltrating cells, differentially impairs CNS integrity and may contribute to the multiplicity of late neurological disorders observed in this viral mouse model.

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Section: Vol 75 2001 Mmp/timp Imbalance In Cdv-infected Brain Strucsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Morbillivirus Infection of the Mouse Central Nervous System Induces Region-Specific Upregulation of MMPs and TIMPs Correlated to Inflammatory Cytokine Expression

Khuth

Akaoka

Pagenstecher

et al. 2001

J Virol

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“…Access to the brain is strictly controlled by blood-brain interfaces, blood vessels and the choroid plexus, and accumulation in neural tissue may result from the enhanced entry/reduced exit rates of T cells from the brain (Kleine and Benes, 2006;Bechmann et al, 2007;Engelhardt and Ransohoff, 2005). The activation process has a dramatic effect on this pathway, in particular by modulating the expression of the adhesion molecules, metalloproteases and chemokine receptors required for lymphocyte transendothelial migration and crawling in inflamed tissue del Pozo et al, 1995;Giraudon et al, 1997;Lane et al, 2000;Strazielle et al, 2003). As a result, more resting T-cells are found in lymphoid organs while activated T-cells mainly target nonlymphoid organs, including brain (Westermann et al, 2005).…”

Section: -Discussionmentioning

confidence: 99%

High CRMP2 expression in peripheral T lymphocytes is associated with recruitment to the brain during virus-induced neuroinflammation

Vuaillat

Varrin‐Doyer

Bernard

et al. 2008

Journal of Neuroimmunology

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“…TNF-␣, in particular, has previously been shown to be cytotoxic to oligodendrocytes and has been shown to sensitize oligodendrocytes to apoptosis in the spinal cord of HTLV-1-infected WKAH rats (21,22). TNF-␣ has been shown to adversely affect glutamate metabolism and expression of matrix metalloproteinase in astrocytes in transient contact with HTLV-1-infected T cells, and this has been hypothesized to result in the breakdown of the structural and functional integrity of the CNS (16,17). The induction of matrix metalloproteinases has been implicated in extracellular matrix degradation and inflammation, and this can result in increased permeability of the BBB and facilitate enhanced migration of HTLV-1-infected cells into the CNS (18,64).…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory Cytokine Gene Induction by Human T-Cell Leukemia Virus Type 1 (HTLV-1) and HTLV-2 Tax in Primary Human Glial Cells

Banerjee¹,

Rochford²,

Antel

et al. 2007

J Virol

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Infection with human T-cell leukemia virus type 1 (HTLV-1) can result in the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic inflammatory disease of the central nervous system (CNS). HTLV-2 is highly related to HTLV-1 at the genetic level and shares a high degree of sequence homology, but infection with HTLV-2 is relatively nonpathogenic compared to HTLV-1. Although the pathogenesis of HAM/TSP remains to be fully elucidated, previous evidence suggests that elevated levels of the proinflammatory cytokines in the CNS are associated with neuropathogenesis. We demonstrate that HTLV-1 infection in astrogliomas results in a robust induction of interleukin-1␤ (IL-1␤), IL-1␣, tumor necrosis factor alpha (TNF-␣), TNF-␤, and IL-6 expression. HTLV encodes for a viral transcriptional transactivator protein named Tax that also induces the transcription of cellular genes. To investigate and compare the effects of Tax1 and Tax2 expression on the dysregulation of proinflammatory cytokines, lentivirus vectors were used to transduce primary human astrocytomas and oligodendrogliomas. The expression of Tax1 in primary human astrocytomas and oligodendrogliomas resulted in significantly higher levels of proinflammatory cytokine gene expression compared to Tax2. Notably, Tax1 expression uniquely sensitized primary human astrocytomas to apoptosis. A Tax2/Tax1 chimera encoding the C-terminal 53 amino acids of the Tax1 fused to the Tax2 gene (Tax 221 ) demonstrated a phenotype that resembled Tax1, with respect to proinflammatory cytokine gene expression and sensitization to apoptosis. The patterns of differential cytokine induction and sensitization to apoptosis displayed by Tax1 and Tax2 may reflect differences relating to the heightened neuropathogenicity associated with HTLV-1 infection and the development of HAM/TSP.Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of a slow progressive neurological disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (42). Although most HTLV-1-infected individuals remain asymptomatic carriers, an estimated 5 to 10% of HTLV-1-infected individuals develop HAM/TSP. HTLV-2 was originally isolated from a patient with an atypical hairy cell leukemia and shares ca. 70% sequence homology with HTLV-1. To date, HTLV-2 infection has been rarely and controversially linked to the development of neurodegenerative diseases (2, 30).Cytokines play a critical role in physiological processes in the central nervous system (CNS), including establishing and maintaining normal homeostasis, as well as mediating inflammatory and immune responses. Cytokines have also been implicated as being the major mediators of demyelination in the CNS, resulting in a variety of inflammatory and neoplastic diseases (1). Elevated levels of tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), IL-1␣, and IL-6 have previously been detected in the cerebrospinal fluid of HAM/TSP patients (28,40,57), suggesting that increased expression of these proi...

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Cytokines secreted by glial cells infected with HTLV-I modulate the expression of matrix metalloproteinases (MMPs) and their natural inhibitor (TIMPs): possible involvement in neurodegenerative processes

Cited by 40 publications

References 1 publication

Morbillivirus Infection of the Mouse Central Nervous System Induces Region-Specific Upregulation of MMPs and TIMPs Correlated to Inflammatory Cytokine Expression

Morbillivirus Infection of the Mouse Central Nervous System Induces Region-Specific Upregulation of MMPs and TIMPs Correlated to Inflammatory Cytokine Expression

High CRMP2 expression in peripheral T lymphocytes is associated with recruitment to the brain during virus-induced neuroinflammation

Proinflammatory Cytokine Gene Induction by Human T-Cell Leukemia Virus Type 1 (HTLV-1) and HTLV-2 Tax in Primary Human Glial Cells

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