Promoter‐specific induction of the phosphatase SHP‐1 by viral infection and cytokines in CNS glia

AbstractWe have previously shown that the protein tyrosine phosphatase SHP‐1 is highly expressed in CNS glia and is an important modulator of cytokine signaling. As such, mice genetically lacking SHP‐1 display constitutive myelin abnormalities, severe virus‐induced demyelinating disease, and defects in innate anti‐viral responses in the CNS. In this study, we show the differential distribution of the SHP‐1 promoter‐specific transcripts and demonstrate that several cytokines significantly induce SHP‐1 expression in CNS glia. Consistent with these cytokine effects, infection with a neurotropic virus both in vitro and in vivo up‐regulates SHP‐1 transcripts and protein in CNS cells. Using CNS glial cultures of gene knockout mice, we show that interferons‐β and interferons‐γ act through STAT‐1 and interferon regulatory factor‐1 to induce the SHP‐1 promoter I transcripts. Conversely, interferons‐β and IL‐6 act through STAT‐3 to induce SHP‐1 promoter II transcripts. This study demonstrates that interferons and other cytokines associated with virus infections in the CNS can significantly induce the expression of SHP‐1 through STAT‐1/3 activity and provides a better understanding of the molecular mechanisms regulating cytokine‐induced expression important for multiple homeostatic functions of SHP‐1 in the CNS.