CYTOKINE-INDUCED CHANGES IN THE ABILITY OF ASTROCYTES TO SUPPORT MIGRATION OF OLIGODENDROCYTE PRECURSORS AND AXON GROWTH

Repair of demyelination in the CNS requires that oligodendrocyte precu rsors (OPs) migrate, divide and then myelinate. Repair of axon damage requires axonal regeneration. Limited remyelination and axon regenerat ion occurs soon after injury, but usually ceases in a few days. In viv o and in vitro experiments have shown that astrocytic environments are not very permissive for migration of OPs or for axonal re-growth. Yet remyelination and axon sprouting early after injury occurs in associa tion with astrocytes, while later astrocytes can exclude remyelination and prevent axon regeneration. A large and changing cast of cytokines are released following CNS injury, so we investigated whether some of these alone or in combination can affect the ability of astrocytes to support migration of OPs and neuritic outgrowth. Interleukin (IL) 1 a lpha, tumour necrosis factor alpha, transforming growth factor (TGF) b eta, basic fibroblast growth factor (bFGF), platelet-derived growth fa ctor and epidermal growth factor alone exerted little or no effect on migration of OPs on astrocytes, whereas interferon (IFN) gamma was inh ibitory. The combination of IL-1 alpha bFGF was found to be pro-migrat ory, and this effect could be neutralized by TGF beta. We also examine d neuritic outgrowth from dorsal root ganglion explants in three-dimen sional astrocyte cultures treated with cytokines and found that IL-1 a lpha + bFGF greatly increased axon outgrowth and that this effect coul d be blocked by TGF beta and IFN gamma. All these effects were absent or much smaller when OP migration or axon growth was tested on laminin , so the main effect of the cytokines was via astrocytes. The cytokine effects did not correlate with expression on astrocytes of laminin, f ibronectin, tenascin, chondroitin sulphate proteoglycan, N-cadherin, p olysialyated NCAM (PSA-NCAM), tissue plasminogen activator (tPA) or ur okinase (uPA).