The prevailing view of the astrocytic response to injury is that reactive astrocytes impede the regenerative process by forming scar tissue. As the levels of many cytokines dramatically increase following CNS insult and as this increase in cytokine expression precedes the production of the glial scar, a longstanding view has been that cytokines diminish neuronal survival and regeneration by stimulating the formation of astrogliotic scar tissue. However, there is a wealth of data indicating that cytokines 'activate' astrocytes, and that cytokinestimulated astrocytes can promote the recovery of CNS function. Supporting evidence demonstrates that cytokine-activated astrocytes produce energy substrates and trophic factors for neurons and oligodendrocytes, act as free radical and excess glutamate scavengers, actively restore the blood-brain barrier, promote neovascularization, restore CNS ionic homeostasis, promote remyelination and also stimulate neurogenesis from neural stem cells. Accordingly, a re-assessment of cytokineactivated astrocytes is necessary. Here, we review studies that promote the thesis that cytokines elicit potent neuroprotective and regenerative responses from astrocytes. Keywords: ciliary neurotrophic factor, gliosis, interleukin-1, microglia. J. Neurochem. (2004) 89, 1092-1100. Astrocytes are the major support cells of the CNSAstrocytes are dynamic cells that maintain homeostasis in the undamaged CNS. Astrocytes express numerous receptors that enable them to respond to virtually all known neuroactive compounds, including neurotransmitters, neuropeptides, growth factors, cytokines, small molecules and toxins. These receptors enable astrocytes to not only participate in signal processing, but to function as sentinels. Astrocytes also establish and maintain CNS boundaries, including the blood-brain barrier (BBB) and the glial limitans, through interactions with endothelial and leptomeningeal cells. Given their important roles in establishing and maintaining CNS homeostasis, an adaptive response by astrocytes to tissue damage should be expected. Indeed, when astrocytes sense that the homeostasis of the brain or spinal cord has been disrupted, their metabolic activity increases, as well as their production of growth and trophic factors; thus endowing them with a greater capacity to protect other brain cells from energy depletion, toxic-free radicals, ammonia, metals and calcium overload. Additionally, after injury, cytokine-activated astrocytes promote the reformation of essential barriers and reestablishment of CNS ionic homeostasis.

Studies have shown that cytokines released following CNS injury can affect the supportive or cytotoxic functions of microglia. Interleukin-6 (IL-6)-family cytokines are among the injury factors released. To understand how microglia respond to IL-6 family cytokines, we examined the effects of ciliary neurotrophic factor (CNTF) and IL-6 on primary cultures of rat microglia. To assess the functional state of the cells, we assayed the expression of tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta), and cyclooxygenase 2 (COX-2) following stimulation. We show that CNTF reduces COX-2 levels, whereas IL-6 increases the expression of IL-1beta, TNFalpha, and Cox-2. We also examined trophic factor expression and found that CNTF enhances glial cell-line derived neurotrophic factor (GDNF) mRNA and protein secretion, whereas IL-6 has no effect. Correspondingly, conditioned media from CNTF-stimulated microglia promote motor neuron survival threefold beyond controls, whereas IL-6-stimulated microglia decrease neuronal survival twofold. To understand better the signaling mechanisms responsible for the opposite responses of these IL-6-family cytokines, we examined STAT-3 and ERK phosphorylation in CNTF- and IL-6-stimulated microglia. IL-6 markedly increases STAT-3 and ERK phosphorylation after 20 min of treatment, whereas these signal transducers are weakly stimulated by CNTF across a range of doses. We conclude that CNTF modifies microglial activation to support neuronal survival and that IL-6 enhances their capacity to do harm, as a result of different modes of intracellular signaling.