Cytokines which signal through the LIF receptor and their actions in the nervous system

Abstract

A number of different cytokines, each initially characterized on the basis of very different biological activities, all have very similar signalling pathways and share a similar tertiary structure. These cytokines include leukaemia inhibitory factor, ciliary neuronotrophic factor, oncostatin M, growth-promoting activity and cardiotrophin 1. They all have been found to regulate a number of properties of cells of the developing and mature nervous system in vitro and thus are neuroregulatory cytokines. The actions of these cytokines include regulation of neurotransmitter phenotype, differentiation of neuronal precursor cells both in the peripheral nervous system and in the spinal cord, survival of differentiated neurons, and regulation of development of both astrocytes and oligodendrocytes. In addition, studies in animal models show that these factors can rescue sensory and motor neurons from axotomy-induced cell death, which suggests that they can act as trauma factors for injured neurons. Analysis of the expression patterns of the different neuroregulatory cytokines and their receptors reveals that the receptors are expressed throughout nervous system development and following trauma, whereas the cytokines show temporal and spatial specific expression patterns. This is consistent with the idea that specific cytokines have specific roles in neural development and repair, but that their signalling pathways are shared. The phenotypes of the receptor knockouts show clear deficits in nervous system development, indicating a crucial role for LIF receptor signalling. Knockouts of individual cytokines are less dramatic, but LIF and CNTF knockouts do reveal deficits in maintenance of motor neurons or following trauma. Thus, whereas LIF and CNTF have clear roles in maintenance and following trauma, it is unclear which of the cytokines is involved in nervous system development. In clinical terms, these findings add further support to the use of these cytokines in nervous system trauma and disease.