Inflammatory cytokines IL-1 beta and TNF-alpha regulate p75(NTR) expression in CNS neurons and astrocytes by distinct cell-type-specific signalling mechanisms

The p75(NTR) (where NTR is neurotrophin receptor) can mediate many distinct cellular functions, including cell survival and apoptosis, axonal growth and cell proliferation, depending on the cellular context. This multifunctional receptor is widely expressed in the CNS (central nervous system) during development, but its expression is restricted in the adult brain. However, p75(NTR) is induced by a variety of pathophysiological insults, including seizures, lesions and degenerative disease. We have demonstrated previously that p75(NTR) is induced by seizures in neurons, where it induces apoptosis, and in astrocytes, where it may regulate proliferation. In the present study, we have investigated whether the inflammatory cytokines IL (interleukin)-1 beta and TNF-alpha (tumour necrosis factor-alpha), that are commonly elevated in these pathological conditions, mediate the regulation of p75(NTR) in neurons and astrocytes. We have further analysed the signal transduction pathways by which these cytokines induce p75(NTR) expression in the different cell types, specifically investigating the roles of the NF-kappa B (nuclear factor kappa B) and p38 MAPK (mitogen-activated protein kinase) pathways. We have demonstrated that both cytokines regulate p75(NTR) expression; however, the mechanisms governing this regulation are cytokine-and cell-type specific. The distinct mechanisms of cytokine-mediated p75(NTR) regulation that we demonstrate in the present study may facilitate therapeutic intervention in regulation of this receptor in a cell-selective manner.