Astrocyte activation is a ubiquitous hallmark of the damaged brain and has been suggested to play an important regulatory role in the activation, survival, and regeneration of adjacent neurons, microglia, and oligodendrocytes. Little is known, however, about the endogenous signals that lead to this activation of astrocytes. Here we examined the regulation of interleukin 6 (IL6), a proinflammatory cytokine, its receptors, and the effects of IL6-deficiency in a model of traumatic central nervous system injury in the axotomized mouse facial motor nucleus. Facial nerve transection led to a massive but transient upregulation of IL6 mRNA in the disconnected motor nucleus, while IL6-receptor subunits were constitutively expressed on motoneurons and astrocytes. Absence of IL6 in genetically IL6-deficient mice led to massive reduction in the number of activated GFAP-positive astrocytes, a more moderate decrease in microglial activation and proliferation, and an increase in the late neuronal response to axotomy. These results emphasize the role of IL6 in the global regulation of neurons, astrocytes, and microglia and their activation in the injured nervous system.