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 cell-specific heterogeneity of responses to IFNγ.