INFLAMMATORY CYTOKINES INTERACT TO MODULATE EXTRACELLULAR-MATRIX AND ASTROCYTIC SUPPORT OF NEURITE OUTGROWTH

Following injury to the central nervous system, an astroglial scar for ms that is thought to impede neuronal regeneration and recovery of fun ction. It is our hypothesis that inflammatory cytokines act upon astro cytes to alter their biochemical and physical properties, which may in turn be responsible for failed neuronal regeneration. We have therefo re examined the interactions of two cytokines with prominent actions f ollowing injury, interferon-gamma (IFN-gamma) and basis fibroblast gro wth factor (FGF2), in modulating the extracellular matrix and prolifer ation of astrocytes in culture. We also evaluated the effects of these cytokines on the ability of astrocytes to support the growth of neuri tes. IFN-gamma significantly inhibited the proliferation of rat cortic al astrocytes both in serum-free and serum-containing media as measure d by [H-3]thymidine incorporation. Furthermore, IFN-gamma also antagon ized FGF2-induced proliferation. In parallel, IFN-gamma reduced the le vels of the ECM molecules tenascin, laminin, and fibronectin as evalua ted by Western blot analysis and immunocytochemistry. Similarly, IFN-g amma 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 antagoniz ed 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 th phosphorylation of mitogen-activated prot ein kinase, suggesting that the interaction is at the level of transcr iptional regulation or that an alternate pathway is involved. These re sults support the hypothesis that inflammatory cytokines interact to m odulate several facets of the gliotic response and such interactions m ay be important in creating the biochemical and physical properties of the glial scar. (C) 1997 Academic Press.