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It is an open question to what extent neuroprotective mechanisms involving neurotrophic proteins are activated after central nervous system (CNS) lesions. Results from previous studies have indicated that ciliary neurotrophic factor (CNTF) and other members of the family of gp130-associated cytokines have neuroprotective effects on septohippocampal projection neurons axotomized by fimbria-fornix transection (FFT). Here we demonstrate that the transcription factor STAT3, a component of the primary cytokine signal transduction pathway, is transiently activated after FFT in the medial septum and in the lateral septum deafferented by the lesion. Immunocytochemical double-labeling showed nuclear signals for phosphorylated STAT3 in both types (GABAergic and cholinergic) of axotomized medial septal neurons around day 4 postlesion. This response temporally coincided with the cell-type-specific upregulation of the cytokine receptor components CNTF receptor alpha and LIF receptor beta in the same neurons. However, neuronal STAT3-activation was not abolished in CNTF- or LIF-deficient mouse mutants. Furthermore, lesion-induced STAT3 signaling was also found in reactive GFAP-positive astrocytes of the medial and lateral septum. Interestingly, basal GFAP expression was reduced but postlesional upregulation was markedly enhanced in CNTF(-/-) animals. These results demonstrate transient activation of cytokine signaling after CNS lesion and suggest that gp130-associated cytokines have multiple functions in the lesioned CNS by directly acting on axotomized neurons and on reactive astrocytes.