IL-6-type cytokines enhance epidermal growth factor-stimulated astrocyte proliferation

Proliferating astrocytes are frequently observed in diseased and injured brains. These newly generated astrocytes are necessary to reestablish the barriers that isolate the CNS from the rest of the body; however, they also create a matrix that inhibits regeneration and remyelination. Therefore, it is important to understand the mechanisms that enable a terminally differentiated astrocyte to reenter the cell cycle. Ciliary neurotrophic factor (CNTF), interleukin-6 (IL-6), transforming growth factor-alpha (TGF-alpha), and fibroblastic growth factor-2 (FGF-2) are four cytokines that are rapidly elevated in damaged neural tissue. These cytokines also have been implicated in glial scar formation. We sought to determine whether IL-6 and CNTF stimulate astroglial proliferation alone or in combination with other mitogens. Intraparenchymal CNTF modestly increased the number of proliferating cell nuclear antigen (PCNA) and glial fibrillary acidic protein (GFAP) double positive astrocytes when introduced by stereotactic injection into the adult rat brain. When applied directly to highly enriched rat forebrain astrocyte cultures, neither CNTF nor IL-6-stimulated DNA synthesis. Therefore, they are not astroglial mitogens. However, both cytokines synergized with epidermal growth factor (EGF), increasing its mitogenicity by approximately twofold. Astrocytes that had been "aged" for at least 3 weeks in vitro became refractory to EGF; however, when these "aged" astrocytes were pretreated with either IL-6 or CNTF for as little as 2 h, they became competent to reenter the cell cycle upon exposure to EGF. These data suggest that IL-6 type cytokines, likely by activating STAT family transcription factors, induce the expression of signaling molecules that endow resting astrocytes with the competence to respond to mitogens and to reenter the cell cycle.