Altered levels of STAT1 and STAT3 influence the neuronal response to interferon gamma

Abstract

As immune responses in the CNS are highly regulated, cell-specific differences in IFNγ signaling may be integral in dictating the outcome of host cell responses. In comparing the response of IFNγ-treated primary neurons to control MEF, we observed that neurons demonstrated lower basal expression of both STAT1 and STAT3, the primary signal transducers responsible for IFNγ signaling. Following IFNγ treatment of these cell populations, we noted muted and delayed STAT1 phosphorylation, no detectable STAT3 phosphorylation, and a 3-10-fold lower level of representative IFNγ-responsive gene transcripts. Moreover, in response to a brief pulse of IFNγ, a steady increase in STAT1 phosphorylation and IFNγ gene expression over 48 h was observed in neurons, as compared to rapid attenuation in MEF. These distinct response kinetics in IFNγ-stimulated neurons may reflect modifications in the IFNγ negative feedback loop, which may provide a mechanism for the cellspecific heterogeneity of responses to IFNγ.

Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge

“…Although these neurons have low basal expression of many ISGs, their induction is appreciable after viral infection. The role or evolutionary advantage of lower homeostatic expression of key signaling molecules in neurons remains to be clearly defined (31,36). While the well-studied ISG product Bst2 was significantly induced in primary neurons and in vivo, this protein appears to be dispensable for survival after neurotropic infection.…”

“…Functional clearance of MV from the CNS of NSE-CD46 ϩ mice is noncytolytic and dependent on both T cells and gamma interferon (IFN-␥) (29,30). Interestingly, neurons differ fundamentally in the basal levels of key signaling molecules that are required for ISG induction compared to mouse embryonic fibroblasts (MEFs) (31). During the course of previous studies, we identified numerous genes that were synthesized in primary hippocampal neurons and MEFs following IFN-␥ treatment.…”

STAT1-Independent Control of a Neurotropic Measles Virus Challenge in Primary Neurons and Infected Mice

“…IFN-g can act directly upon neurons to induce an antiviral state, as demonstrated by the direct antiviral ability of IFN-g to limit MV replication in purified CD46 + neurons cultured ex vivo (3). Surprisingly, however, the neuronal signaling response to IFN-g treatment was distinct from that observed in control mouse embryonic fibroblasts (MEFs) (35). Specifically, neurons responded to IFN-g with delayed and attenuated STAT1 expression and activation kinetics in comparison with control fibroblasts.…”

“…Primary hippocampal neurons were prepared from embryonic (E15-16) mice, as previously described (35)(36)(37)(38). Neurons were plated on 15-mm glass coverslips or in 12-well plates coated with poly-L-lysine (Sigma-Aldrich) at a density of 2.5 3 10 5 cells/well, unless otherwise noted.…”

Blue Moon Neurovirology: The Merits of Studying Rare CNS Diseases of Viral Origin

“…For example, many mitotically active cells, such as fibroblasts, respond to IFNγ with rapid activation of STAT1, followed by inactivation of STAT1 by suppressor of cytokine signaling 1. In contrast, primary hippocampal neurons respond to IFNγ with delayed and attenuated STAT1 phosphorylation and expression, though the attenuated activation is sustained for days after the initial IFNγ exposure (Rose et al 2007). Since IFNγ signaling via STAT1 is often associated with antiproliferative and proapoptotic effects, the attenuation in STAT1 signaling in neurons may confer a survival advantage.…”