ADAMTS-1 and -4 are up-regulated following transient middle cerebral artery occlusion in the rat and their expression is modulated by TNF in cultured astrocytes

Abstract

ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzymes are a recently described group of metalloproteinases. The substrates degraded by ADAMTS-1, -4 and -5 suggests that they play a role in turnover of extracellular matrix in the central nervous system (CNS). ADAMTS-1 is also known to exhibit anti-angiogenic activity. Their main endogenous inhibitor is tissue inhibitor of metalloproteinases (TIMP)-3.The present study was designed to investigate ADAMTS-1, -4 and -5 and TIMP-3 expression after experimental cerebral ischaemia and to examine whether cytokines known to be up-regulated in stroke could alter their expression by astrocytes in vitro.Focal cerebral ischaemia was induced by transient middle cerebral artery occlusion in the rat using the filament method.Our results demonstrate a significant increase in expression of ADAMTS-1 and -4 in the occluded hemisphere but no significant change in TIMP-3. This was accompanied by an increase in mRNA levels for interleukin (IL)-1β, IL-1 receptor antagonist (IL1ra) and tumour necrosis factor (TNF). ADAMTS-4 mRNA and protein was upregulated by TNF in primary human astrocyte cultures. The increased ADAMTS-1 and -4 in experimental stroke, together with no change in TIMP-3, may promote ECM breakdown after stroke, enabling infiltration of inflammatory cells and contribute to brain injury. In vitro studies suggest that the in vivo modulation of ADAMTS-1 and -4 may be controlled in part by TNF.3

C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

“…Illustrated by atherosclerosis, many inflammatory diseases comprise extracellular matrix remodeling processes that are regulated at different levels by proinflammatory cytokines such as IL-1␤ and TNF-␣ and require metalloproteinase activity. IL-1␤ and TNF-␣ are known to induce Adamts-1 mRNA in different cell types (57,58); however, the precise transcriptional mechanism involved awaits identification. Similar to Ang-II, we have identified C/EBP␤ as the chief mediator of Adamts-1 regulation by IL-1␤ and TNF-␣ in vascular cells.…”

Extracellular matrix of the central nervous system: from neglect to challenge

“…After a kainateinduced excitotoxic insult, a transient up-regulation of ADAMTS-4 and ADAMTS-1 coincides with a marked increase of brevican proteolysis (Mayer et al 2005;Yuan et al 2002). A similar reaction is also observed in an experimental model of cerebral ischemia (Cross et al 2006). Moreover, motor axon disruption induces the ADAMTS-1 production in the aVected neurons and there is growing evidence that the same enzyme is also over-expressed in association with various neurodegenerative disorders (Miguel et al 2005;Satoh et al 2000).…”

ADAMTS1 Is a Unique Hypoxic Early Response Gene Expressed by Endothelial Cells

“…Bevitt et al (29) reported that ADAMTS1 was induced by TNF␣ stimulation in ARPE. Cross et al (30) reported that ADAMTS1 mRNA was increased by IL-1␤ and TNF in cultured astrocytes; however, Kalinski et al (31) reported that ADAMTS1 mRNA was decreased by IL-1␤ in the human chondrosarcoma cell line C3842. In fact, we have previously reported that IL-1␤ stimulation rather decreased ADAMTS1 mRNA in another chondrosarcoma cell line, OUMS-27 (32).…”