Reprogramming of TIMP‐1 and TIMP‐3 expression profiles in brain microvascular endothelial cells and astrocytes in response to proinflammatory cytokines

Bugno, Marcin; Witek, Barbara; Bereta, Joanna; Bereta, Michał; Edwards, Dylan R.; Kordula, Tomasz

doi:10.1016/s0014-5793(99)00323-3

Cited by 68 publications

(70 citation statements)

References 37 publications

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“…It is unexpected that TIMP-1/-2 expression was decreased after GM6001 treatment. Previous reports have documented that inflammatory cytokines (such as Interleukin-1 beta, tumor necrosis factor-alpha, Interleukin-6) are important to stimulate TIMPs expression (Bugno et al 1999;Pagenstecher et al 2000). It is possible that the influence of GM6001 on TIMPs expression is because of the secondary effects by GM6001-induced neuroprotection, instead of the direct effects.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Chen

Hartman

Ayer

et al. 2009

Journal of Neurochemistry

109

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Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which are capable of degrading many types of extracellular matrix proteins and involved in the process of tissue remodeling in various pathologic conditions, including inflammatory diseases, tumor cell invasion, and angiogenesis. Previous studies suggest that MMPs, in particular MMP-2 and MMP-9, are deleterious in the brain after stroke (Power et al. 2003;Svedin et al. 2007). In acute stage after ischemic stroke, the effect of MMP activity is correlated to degradation of neurovascular matrix and opening of blood-brain barrier (BBB), which promotes vasogenic edema and results in neurological deficits. However, recent studies suggest that MMPs were also indicated to be involved in the repairing phase in the delayed stage after cerebral ischemia, including neuroblasts migration and neuronal plasticity (Lee et al. 2006;Zhao et al. 2006 AbstractThe present study was designed to investigate the role of matrix metalloproteinases (MMPs) in the immature brain and the long term effects of early MMPs inhibition after hypoxicischemic (HI) injury. HI was induced by unilateral ligation of the right carotid artery followed by hypoxia (8% O 2 for 2 h) in P7 rat pups. GM6001, a broad spectrum MMPs inhibitor, was injected (50 mg/kg or 100 mg/kg) intraperitoneally at 2 h and 24 h after HI injury. Blood-brain barrier (BBB) integrity, brain edema, MMP-2/-9 activity, TIMP-1/-2 and tight junction protein (TJP) level were evaluated using IgG staining, Evan's blue extravasation, brain water content, zymography and western blot. Doxycycline, another MMPs inhibitor, was injected (10 mg/kg or 30 mg/kg) intraperitoneally at 2 h after HI, then BBB integrity and brain edema were measured at 48 h post-HI using brain water content measurement and IgG staining. The long-term effects of early MMPs inhibition (GM6001, 100 mg/ kg) were evaluated by neurobehavioral tests, body weight, and brain atrophy measurement. GM6001 attenuated brain edema and BBB disruption at the dosage of 100 mg/kg. MMP-2 activity increased at 24 h and peaked at 48 h after HI, whereas MMP-9 activity peaked at 24 h and tapered by 48 h after HI. MMP-9/-2 activities were significantly attenuated by GM6001 at 24 h and 48 h after HI. The degradation of TJPs (ZO-1 and occludin) at 48 h after HI was reversed by GM6001 treatment. Early MMPs inhibition had long-term effects that attenuated ipsilateral brain tissue loss, and improved neurobehavioral outcomes after HI. These results suggest that early MMPs inhibition with a broad-spectrum inhibitor provides both acute and long-term neuroprotection in the developing brain by reducing TJPs degradation, preserving BBB integrity, and ameliorating brain edema after neonatal HI injury. Keywords: blood-brain barrier, hypoxic/ischemic, matrix metalloproteinase, neonatal.

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Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Chen

Hartman

Ayer

et al. 2009

Journal of Neurochemistry

109

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“…Inducted TIMP-1 expression in a brain endothelial cell line could preserve the brain endothelial barrier function in vitro (Förster et al, 2007). In brain microvascular endothelial cells, the expression of TIMP-1 was dramatically increased by major proinflammatory cytokines, especially by the combination with interleukin-1b and tumor necrosis factor-a (Bugno et al, 1999). Tissue inhibitor of metalloproteinase-1 has also been considered as an immediate early gene.…”

Section: Discussionmentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinases Protect Blood—Brain Barrier Disruption in Focal Cerebral Ischemia

Fujimoto

Takagi

Aoki

et al. 2008

J Cereb Blood Flow Metab

138

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Enhanced matrix metalloproteinases (MMPs) can cause vasogenic edema and hemorrhagic transformation after cerebral ischemia, and affect the extent of ischemic injury. We hypothesized that the endogenous MMP inhibitors, tissue inhibitor of MMPs (TIMPs), were essential to protect against blood-brain barrier (BBB) disruption after ischemia by regulating the activities of MMPs. We confirmed the transition of MMP-2 and MMP-9, and the TIMPs family after 30 mins of middle cerebral artery occlusion, and elucidated the function of TIMP-1 and TIMP-2 in focal ischemia, using TIMP-1 À/À and TIMP-2 À/À mice. TIMP-1 mRNA expression was gradually increased until 24 h after reperfusion. In TIMP-1 À/À mice, MMP-9 protein expression and gelatinolytic activity were significantly more augmented after cerebral ischemia than those in WT mice, and were accompanied by exacerbated BBB disruption, neuronal apoptosis, and ischemic injury. In contrast, TIMP-2 gene deletion mice exhibited no significant difference in MMP expressions and the degree of ischemic injury despite an increased Evans blue leakage. These results suggest that TIMP-1 inhibits MMP-9 activity and can play a neuroprotective role in cerebral ischemia.

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“…This may provide a mechanism for controlling the proteolytic activity of enzymes under TIMP control. For example when the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) are applied simultaneously to brain endothelial cells (ECs), TIMP3 expression is almost completely blocked (16).…”

Section: Introductionmentioning

confidence: 99%

Expression of ADAMTS-1, ADAMTS-4, ADAMTS-5 and TIMP3 by hepatocellular carcinoma cell lines

Turner

Mangnall

Bird

et al. 2012

International Journal of Oncology

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Abstract.Little is known about the expression or role of ADAMTS-1, -4 and -5 and their endogenous inhibitor TIMP3 in the liver in physiological and pathological conditions. Their expression was, therefore, investigated in the hepatocellular carcinoma cell lines HepG2 and HuH-7 using qRT-PCR and western blotting, and their cellular localisation by immunocytochemistry. Cytokine treatments were used to assess mRNA and protein modulation. ADAMTS-1, -4, -5 and TIMP3 mRNA and protein were detected in both HepG2 and HuH-7 cells. IL-1β and IL-6 treatments significantly modulated ADAMTS-1 mRNA expression and IL-1β treatment ADAMTS-4 mRNA expression in HepG2 cells. Modulations of mRNA by ≥5-fold did not translate to increased protein expression. This study showed that ADAMTS-1, -4, -5 and TIMP3 were expressed at differential levels in hepatocellular carcinoma cell lines. The pro-inflammatory cytokines IL-1β, TNF-α or IL-6 induced changes in mRNA expression, although these did not translate to the protein level. IntroductionHepatocellular carcinoma (HCC) is the most common primary malignant tumour occurring in the liver which accounts for 80-90% of all primary liver cancers (1). In many cases, the neoplastic transformation of hepatocytes results from accumulation of genetic changes during enhanced cell proliferation in the injured liver in response to paracrine growth factor and cytokine stimulation (2). HCCs have a considerable capacity for vascular invasion, with metastasis and recurrence being the major factors associated with the poor prognosis of HCC (3).Proteolytic modification of cell surface proteins and extracellular matrix (ECM) plays a pivotal role in cancer development and metastasis. Proteolytic enzymes are involved in several processes, at the cellular and organism level, which are dysregulated in cancer, e.g. cell adhesion and migration, cell invasion and angiogenesis. In particular, they mediate tumour invasion at several stages, e.g. detachment of cells from the primary tumour, crossing vessel walls and extravasation into target organs. This involves attachment of oncogenically transformed cells to the ECM followed by its degradation and movement of invading cells through the damaged ECM (4,5).Expression and activity of several classes of proteolytic enzymes have been shown to be modified in cancer, including recently discovered a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs). There are 19 ADAMTSs which can be involved in pathological processes such as ECM breakdown and angiogenesis (6). They consist of several domains: the prodomain, metalloproteinase domain, disintegrin-like domain, cysteine-rich domain, thrombospondin type-I repeats (TSRs) and a spacer domain. Several ADAMTSs also contain an additional unique domain(s). They are synthesised as zymogens and after proteolytic processing at the N-terminus to remove the signal sequence and prodomain, they are secreted from cells. For most ADAMTSs this is an important step in their activation. ADAMTSs may also undergo C-terminal proc...

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Reprogramming of TIMP‐1 and TIMP‐3 expression profiles in brain microvascular endothelial cells and astrocytes in response to proinflammatory cytokines

Cited by 68 publications

References 37 publications

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Tissue Inhibitor of Metalloproteinases Protect Blood—Brain Barrier Disruption in Focal Cerebral Ischemia

Expression of ADAMTS-1, ADAMTS-4, ADAMTS-5 and TIMP3 by hepatocellular carcinoma cell lines

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