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, 148 (2), 628-39

Inflammatory Cytokines Interact to Modulate Extracellular Matrix and Astrocytic Support of Neurite Outgrowth

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Inflammatory Cytokines Interact to Modulate Extracellular Matrix and Astrocytic Support of Neurite Outgrowth

N A DiProspero et al. Exp Neurol.

Abstract

Following injury to the central nervous system, an astroglial scar forms that is thought to impede neuronal regeneration and recovery of function. It is our hypothesis that inflammatory cytokines act upon astrocytes to alter their biochemical and physical properties, which may in turn be responsible for failed neuronal regeneration. We have therefore examined the interactions of two cytokines with prominent actions following injury, interferon-gamma (IFN-gamma) and basic fibroblast growth factor (FGF2), in modulating the extracellular matrix and proliferation of astrocytes in culture. We also evaluated the effects of these cytokines on the ability of astrocytes to support the growth of neurites. IFN-gamma significantly inhibited the proliferation of rat cortical astrocytes both in serum-free and serum-containing media as measured by [3H]thymidine incorporation. Furthermore, IFN-gamma also antagonized FGF2-induced proliferation. In parallel, IFN-gamma reduced the levels of the ECM molecules tenascin, laminin, and fibronectin as evaluated by Western blot analysis and immunocytochemistry. Similarly, IFN-gamma also antagonized FGF2-induced tenascin formation. While IFN-gamma-pretreated astrocyte monolayers did not differ from control in their ability to support neurite outgrowth of cortical neurons, it antagonized the enhancement of neurite outgrowth on FGF2-treated monolayers. We demonstrate that IFN-gamma did not alter signal transduction through the FGF2 receptor down to the phosphorylation of mitogen-activated protein kinase, suggesting that the interaction is at the level of transcriptional regulation or that an alternate pathway is involved. These results support the hypothesis that inflammatory cytokines interact to modulate several facets of the gliotic response and such interactions may be important in creating the biochemical and physical properties of the glial scar.

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