RESUMEN
Leukemia inhibitory factor (LIF), a neuropoietic cytokine, has been implicated in the control of neuronal development. We previously reported that LIF plays a critical role in regulating the terminal differentiation of olfactory sensory neurons (OSNs). Here, we demonstrate that LIF plays a complementary role in supporting the survival of immature OSNs. Mature OSNs express LIF, which may be elaborated in a paracrine manner to influence adjacent neurons. LIF null mice display more apoptotic immature neurons than do their wild-type littermates. LIF treatment of dissociated OSNs in vitro significantly reduces the apoptosis of immature OSNs. Double immunocytochemical analysis indicates that the survival of immature OSNs is dependent on the presence of LIF. LIF activates the phosphoinositide 3-kinase (PI3K) pathways and induces the expression of the antiapoptotic molecule Bcl-2 in OSNs, whereas inhibition of the PI3K pathway blocks LIF-dependent OSN survival and Bcl-2 induction. Thus, LIF plays a central role in maintaining the size and integrity of the population of immature neurons within the olfactory epithelium; this population is critical to the rapid recovery of olfactory function after injury. LIF may play a similar role elsewhere in the CNS and thus be important for manipulation of stem cell populations for therapeutic interventions.
Asunto(s)
Supervivencia Celular/fisiología , Factor Inhibidor de Leucemia/metabolismo , Neuronas Receptoras Olfatorias/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Animales , Apoptosis/fisiología , Western Blotting , Células Cultivadas , Cromonas/farmacología , Activación Enzimática , Inhibidores Enzimáticos/farmacocinética , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Factor Inhibidor de Leucemia/genética , Masculino , Ratones , Ratones Noqueados , Morfolinas/farmacología , Mucosa Olfatoria/citología , ARN Mensajero/metabolismo , Transducción de SeñalRESUMEN
Recognition of stereotypic chemical patterns by sentinel cells of the innate immune system provokes a transient deviation from homeostasis, the acute-phase response (APR). Although APR effectors have been identified individually, the complexity of the response suggested that emergent properties would be uncovered by a more comprehensive examination. Our global assessment revealed that approximately 7% of genes in the mouse are mobilized in the hepatic APR to endotoxin. Extensive metabolic adjustments include suppression of pathways for cholesterol, fatty acid, and phospholipid synthesis. Increased expression of genes for innate defense was accompanied by coordinate induction of the MHC class I antigen presentation machinery, illustrating an intersection between innate and adaptive immunity.