Abstract
Neurogenesis continues in the adult brain and in the adult olfactory epithelium. The cytokine, leukaemia inhibitory factor and nitric oxide are both known to stimulate neuronal progenitor cell proliferation in the olfactory epithelium after injury. Our aim here was to determine whether these observations are independent, specifically, whether leukaemia inhibitory factor triggers neural precursor proliferation via the inducible nitric oxide synthase pathway. We evaluated the effects of leukaemia inhibitory factor on inducible form of nitric oxide synthase (iNOS) expression, and cell proliferation in olfactory epithelial cell cultures and olfactory neurosphere-derived cells. Leukaemia inhibitory factor induced expression of iNOS and increased cell proliferation. An iNOS inhibitor and an anti-leukaemia inhibitory factor receptor blocking antibody inhibited leukaemia inhibitory factor-induced cell proliferation, an effect that was reversed by a NO donor. Altogether, the results strongly suggest that leukaemia inhibitory factor induces iNOS expression, increasing nitric oxide levels, to stimulate proliferation of olfactory neural precursor cells. This finding sheds light on neuronal regeneration occurring after injury of the olfactory epithelium.
Highlights
Neurogenesis in the adult nervous system is limited to in a few areas of the brain [1] and to the olfactory epithelium [2,3]
In order to determine whether olfactory neuronal precursor cells are capable of responding to leukaemia inhibitory factor (LIF) by expressing inducible form of nitric oxide synthase (iNOS), the expression of iNOS and LIF receptor (LIFR) was examined in primary cultures of olfactory epithelial cells; these cultures contained only neuronal precursor cells, except for a few supporting cells [19]
A basal level of iNOS mRNA and protein expression was observed in cells grown in control medium, but it increased after 24 h of LIF treatment (Fig. 1A, C)
Summary
Neurogenesis in the adult nervous system is limited to in a few areas of the brain [1] and to the olfactory epithelium [2,3]. Adult neurogenesis is regulated by a variety of neurotrophins [4] and neuropoietic cytokines [5,6]. The leukaemia inhibitory factor (LIF), a member of the gp130 family of neuropoietic cytokines, was originally identified as a macrophage proliferation and differentiation regulating factor [7], but several effects of LIF have been recently determined in neurogenesis. The evidence suggests that LIF is involved in the recruitment of neural stem cells and progenitor cells after injury, which is likely to be the first step towards regeneration. LIF is involved in neurogenesis in the olfactory epithelium, where it stimulates the proliferation of neuronal precursor cells [15]. The LIF receptor (LIFR) is expressed by neuronal precursor cells, neuronal axons and infiltrated macrophages during injury-induced olfactory epithelium regeneration [16,17]
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