Inverse regulation of inducible nitric oxide synthase (iNOS) and arginase I by the protein tyrosine phosphatase SHP-1 in CNS glia
Article first published online: 24 MAR 2006
Copyright © 2006 Wiley-Liss, Inc.
Volume 53, Issue 8, pages 827–835, June 2006
How to Cite
Bonaparte, K. L., Hudson, C. A., Wu, C. and Massa, P. T. (2006), Inverse regulation of inducible nitric oxide synthase (iNOS) and arginase I by the protein tyrosine phosphatase SHP-1 in CNS glia. Glia, 53: 827–835. doi: 10.1002/glia.20344
- Issue published online: 17 APR 2006
- Article first published online: 24 MAR 2006
- Manuscript Accepted: 17 FEB 2006
- Manuscript Received: 2 NOV 2005
- NIH-NINDS. Grant Number: RO1 NS041593-04
- cell signaling;
- innate immunity;
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. © 2006 Wiley-Liss, Inc.