Promoter-specific induction of the phosphatase SHP-1 by viral infection and cytokines in CNS glia.
We 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-beta and interferons-gamma act through STAT-1 and interferon regulatory factor-1 to induce the SHP-1 promoter I transcripts. Conversely, interferons-beta 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.
Christophi
George P
GP
Department of Neurology, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
Hudson
Chad A
CA
Gruber
Ross
R
Christophi
Christoforos P
CP
Massa
Paul T
PT
D000818:Animals; D018188:Cardiovirus Infections / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D018792:Encephalitis, Viral / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009457:Neuroglia / Q000201:enzymology* / Q000821:virology; D011401:Promoter Regions, Genetic / Q000502:physiology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D017945:Theilovirus
D016207:Cytokines; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6