Inverse regulation of inducible nitric oxide synthase (iNOS) and arginase I by the protein tyrosine phosphatase SHP-1 in CNS glia.
We have previously shown that the SH2 domain-containing protein tyrosine phosphatase SHP-1 plays a critical role in controlling virus infection in CNS glia in vivo and in vitro. The present study addressed whether increased virus replication in SHP-1-deficient glia in vitro may be a result of altered expression of inducible nitric oxide synthase (iNOS/NOS2). First, we observed a profound reduction in iNOS protein expression and production of nitric oxide (NO) in response to the viral mimic double-stranded RNA (dsRNA), despite the induction of high levels of iNOS mRNA, in SHP-1-deficient motheaten mouse compared to wild type littermate mouse glia. Because both iNOS expression and NO production are suppressed by multiple pathways involving arginase I activity, it was important that we observed abnormally high constitutive expression of arginase I in cultured glia of SHP-1-deficient compared to wild type mice. Further, both constitutive and IL-4/IL-10-induced expression of arginase I correlated with elevated STAT6 nuclear binding activity, decreased NO production, and increased virus replication in motheaten compared to wild type astrocytes. These findings provide the first evidence of an inverse relationship between NO and arginase I activity regulated by SHP-1 in CNS glia that is relevant to modulation of innate anti-viral responses. Thus, we propose that SHP-1 is a critical regulator of innate immunity to virus infections in CNS cells.
Bonaparte
Kathryn L
KL
Department of Neurology, Upstate Medical University, State University of New York, Syracuse, New York 13210, USA.
Hudson
Chad A
CA
Wu
Charlene
C
Massa
Paul T
PT
D000818:Animals; D001119:Arginase / Q000378:metabolism*; D002490:Central Nervous System / Q000201:enzymology*; D020805:Central Nervous System Viral Diseases / Q000235:genetics / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009457:Neuroglia / Q000201:enzymology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012330:RNA, Double-Stranded / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; D001119:Arginase