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-B 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-B (IB␣SR), or by the knock-down of p65 subunit of NF-B. Binding of activated NF-B (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-B 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.The remodeling of the extracellular matrix (ECM), 2 including the degradation of the ECM by matrix metalloproteinases (MMPs) and its subsequent resynthesis, is critical during normal physiological processes, such as angiogenesis, embryonic development, organ morphogenesis, bone remodeling, and ovulation (1, 2). During these processes the proteolytic activity of MMPs is tightly controlled at the transcriptional level by growth factors, hormones, and cytokines, and at the protein level by proteolytic cleavage of inactive zymogens, and the inhibition by specific inhibitors, including tissue inhibitors of metalloproteinases (TIMPs) (2). The delicate balance between the activities of MMPs and TIMPs is critical to limit deleterious outcomes of uncontrolled degradation, which is manifested in pathological conditions such as periodontal disease, arthritis, tumor cell invasion, fibrosis, and neurodegenerative disorders (2-4). These pathological conditions often represent chronic inflammatory diseases suggesting that inflammatory mediators, including inflammatory cytokines, may disrupt the intricate balance between MMPs and TIMPs.In the central nervous system (CNS), infection and injury induce a histopathological response known as reactive astrogliosis, which is the primary cause of regenerative failure in ...