TWEAK stimulation of astrocytes and the proinflammatory consequences

Astrocytes exert many active roles in brain homeostasis, potentially includ ing the regulation of immune reactions. They possess a substantial aptitude for plasticity and, indeed, functional and phenotypic changes are frequent ly encountered in reactive gliosis observed in brain injuries. The signific ance of reactive astrocytes is still poorly defined, but it is clear that t hese cells are an important source of cytokines in inflamed brain. How tumo r necrosis factor (TNF) and TNF-receptor family members contribute to this reaction is an interesting issue that is currently being explored. It was p reviously shown that reactive astrocytes express high levels of Fas (CD95) and respond to Fas ligand (CD95L) by apoptosis or IL-8 production. TWEAK (A po-3 ligand) is a recently identified member of the TNF family that is prod uced mainly by leukocytes that can infiltrate the inflamed brain and thus i nfluence astrocyte behavior. Here we show that human astrocytes derived fro m different regions of the brain specifically bind TWEAK and are totally re sistant to TWEAK mediated apoptosis. In addition, high amounts of IL-8 and IL-6 were secreted by astrocytes after TWEAK exposure. Finally, expression of cell surface molecules involved in the propagation and/or maintenance of brain inflammation was determined. TWEAK significantly increased ICAM-1 ex pression on astrocytes, whereas no modification was detected in the express ion of Fas, TNFRI, B7-1, or MHC molecules. In conclusion, the proinflammato ry effects induced by TWEAK on astrocytes in culture recapitulate many char acteristics of reactive astrocytes observed in vivo, suggesting that TWEAK could play a significant role in brain inflammation. GLIA 32:102-107 2000. (C) 2000 Wiley-Liss, Inc.