A novel mechanism of tissue inhibitor of metalloproteinases-1 activation by interleukin-1 in primary human astrocytes.
Reactive astrogliosis is the gliotic response to brain injury with activated astrocytes and microglia being the major effector cells. These cells secrete inflammatory cytokines, proteinases, and proteinase inhibitors that influence extracellular matrix (ECM) remodeling. In astrocytes, the expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) is up-regulated by interleukin-1 (IL-1), which is a major neuroinflammatory cytokine. We report that IL-1 activates TIMP-1 expression via both the IKK/NF-kappaB and MEK3/6/p38/ATF-2 pathways in astrocytes. The activation of the TIMP-1 gene can be blocked by using pharmacological inhibitors, including BAY11-7082 and SB202190, overexpression of the dominant-negative inhibitor of NF-kappaB (IkappaBalphaSR), or by the knock-down of p65 subunit of NF-kappaB. Binding of activated NF-kappaB (p50/p65 heterodimer) and ATF-2 (homodimer) to two novel regulatory elements located -2.7 and -2.2 kb upstream of the TIMP-1 transcription start site, respectively, is required for full IL-1-responsiveness. Mutational analysis of these regulatory elements and their weak activity when linked to the minimal tk promoter suggest that cooperative binding is required to activate transcription. In contrast to astrocytes, we observed that TIMP-1 is expressed at lower levels in gliomas and is not regulated by IL-1. We provide evidence that the lack of TIMP-1 activation in gliomas results from either dysfunctional IKK/NF-kappaB or MEK3/6/p38/ATF-2 activation by IL-1. In summary, we propose a novel mechanism of TIMP-1 regulation, which ensures an increased supply of the inhibitor after brain injury, and limits ECM degradation. This mechanism does not function in gliomas, and may in part explain the increased invasiveness of glioma cells.
Wilczynska
Katarzyna M
KM
Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA.
Gopalan
Sunita M
SM
Bugno
Marcin
M
Kasza
Aneta
A
Konik
Barbara S
BS
Bryan
Lauren
L
Wright
Sarah
S
Griswold-Prenner
Irene
I
Kordula
Tomasz
T
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D005786:Gene Expression Regulation; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1