Inflammation in the brain has been implicated in the development and progression of several pathological states of the central nervous system including neurodegenerative disorders such as Alzheimer's disease. Proinflammatory cytokines released during inflammation contribute not only to the progression of the disease but also to the repair processes. This includes release of proteolytic enzymes and their inhibitors, degradation of extracellular matrix, which facilitates attachment/detachment of cells, cell migration, degradation of deposits, and ultimately repopulation of injury sites. At least two proteolytic systems can be implicated in these processes: the plasminogen activator system controlling the generation of plasmin and the metalloproteinases/tissue inhibitor of metalloproteinases (MMPs/TIMPs) system that restrains the activity of MMPs. Recently, we have found that, proinflammatory cytokines and epidermal growth factor (EGF) can drastically regulate the expression of several components of both systems in human astrocytes. Therefore, the current study will focus on recognition and understanding the regulatory mechanisms of proinflammatory cytokines and EGF action in these cells. Specifically, the activation of signaling molecules and transcription factors in EGF- and cytokine-treated human astrocytes will be studied. Mechanisms leading to the activation of the TIMP-1 and PAI-1 (plasminogen activator inhibitor) genes will be analyzed in detail in response to EGF and cytokines. A better understanding of glial proteolysis regulation in the brain may have impact on a wide range of developmental, neoplastic, neurodegenerative and neurovascular diseases.
| Wilczynska, Katarzyna M; Gopalan, Sunita M; Bugno, Marcin et al. (2006) A novel mechanism of tissue inhibitor of metalloproteinases-1 activation by interleukin-1 in primary human astrocytes. J Biol Chem 281:34955-64 |
