Interferon-γ Produced by Microglia and the Neuropeptide PACAP Have Opposite Effects on the Viability of Neural Progenitor Cells

Abstract

Inflammation is part of many neurological disorders and immune reactions may influence neuronal progenitor cells (NPCs) contributing to the disease process. Our knowledge about the interplay between different cell types in brain inflammation are not fully understood. It is important to know the mechanisms and factors involved in order to enhance regeneration and brain repair. We show here that NPCs express receptors for interferon-γ (IFNγ), and IFNγ activates the signal transducer and activator of transcription (STAT) protein-1. IFNγ reduced cell proliferation in NPCs by upregulation of the cell cycle protein p21 as well as induced cell death of NPCs by activating caspase-3. Studies of putative factors for rescue showed that the neuropeptide, Pituitary adenylate cyclase-activating polypeptide (PACAP) increased cell viability, the levels of p-Bad and reduced caspase-3 activation in the NPCs. Medium from cultured microglia contained IFNγ and decreased the viability of NPCs, whilst blocking with anti-IFNγ antibodies counteracted this effect. The results show that NPCs are negatively influenced by IFNγ whereas PACAP is able to modulate its action. The interplay between IFNγ released from immune cells and PACAP is of importance in brain inflammation and may affect the regeneration and recruitment of NPCs in immune diseases. The observed effects of IFNγ on NPCs deserve to be taken into account in human anti-viral therapies particularly in children with higher rates of brain stem cell proliferation.

Immunological regulation of neurogenic niches in the adult brain

“…IFN-γ has shown a dual effect on NSCs, because not only stimulates neuronal differentiation, but also promotes migration and reduces proliferation and cell survival of neural progenitors (Ben-Hur et al, 2003; Wong et al, 2004; Song et al, 2005). Reduction in proliferation and survival activated by IFN-γ receptors is mediated through STAT/1 signaling pathway (Makela et al, 2010). …”

Cutting Edge: IFN-γ Produced by Brain-Resident Cells Is Crucial To Control Cerebral Infection with Toxoplasma gondii

“…In addition to T cells, cells other than T and NK cells need to produce this cytokine to prevent reactivation of the infection in the brain (2). Microglia and astrocytes from the brain have been shown to produce IFN-γ in vitro in response to various stimulations including LPS (3, 4). However, it is unknown whether IFN-γ produced by brain-resident cells including glial cells plays any roles in resistance to cerebral infections with microorganisms including T. gondii .…”

Signal Transducer and Activator of Transcription-5 Mediates Neuronal Apoptosis Induced by Inhibition of Rac GTPase Activity

“…Consistent with these findings, we have shown previously that Rac activity is critical for the survival of primary CGNs (6), and Rac signaling functions to repress a proapoptotic JAK/STAT pathway in these neurons (8). Similarly, studies from other groups support a role for the activation of a prodeath JAK/STAT pathway in neurons (48,49). For instance, Takagi et al (27) reported that STAT1 was phosphorylated on activating tyrosine and serine residues and translocated into neuronal nuclei following ischemic brain injury in mice.…”