Inverse regulation of inducible nitric oxide synthase (iNOS) and arginase I by the protein tyrosine phosphatase SHP-1 in CNS glia

Abstract

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.

Bordetella pertussis Adenylate Cyclase Toxin Blocks Induction of Bactericidal Nitric Oxide in Macrophages through cAMP-Dependent Activation of the SHP-1 Phosphatase

“…cAMP signaling through PKA causes dephosphorylation of AP-1 iNOS expression depends to large extent on the activity of the transcription factor AP-1 (20,21). Therefore, we examined whether cAMP signaling of CyaA affected the regulatory phosphorylation of the c-Fos subunit of AP-1.…”

“…Regulation of NO production in monocytic cells then largely depends on regulation of iNOS gene expression level (19). This results from the interplay of transcription factors, such as NF-kB, the signal transducer and activator of transcription 1 (STAT1), and the AP-1, respectively (20,21). Involvement of the transcription factors NF-kB and AP-1 in iNOS expression further appears to be modulated by the activity of the SHP-1, which was also shown to modulate the activity of the transcription factor STAT1 and of the IRF-1 (22,23).…”

Reactive Nitrogen Species and Hydrogen Sulfide as Regulators of Protein Tyrosine Phosphatase Activity

“…In SHP-1-deficient glia, viral mimic dsRNA was reported to suppress iNOS expression and NO production despite the levels of mRNA for iNOS remaining high, while it induced high expression of arginase I. Similarly, IL-4/IL-10-induced expression of arginase I correlated with decreased NO production and increased virus replication in SHP-1-deficient astrocytes (6). Although the mechanisms remain enigmatic, SHP-1 arises as an important regulator of NO production and, thus, of innate immunity in multiple cell types.…”

“…There is also a potential feedback loop consisting of several PTPs that are shown to directly or indirectly regulate the activity of NOSs, regulating either NOS tyrosine phosphorylation (coupled with changes in their activity) or transcriptional factors responsible for the NOS expression (6,12,16,25,35,36,38,44,65,77,85,87,91). The NOSs produce NO by a conversion of one of the terminal nitrogens of the guanidine group of L-arginine to NO, producing L-citrulline (37).…”

“…Later, PTP1B was also reported to act in tumorigenesis, myeloid differentiation, and macrophage activation, in which it can attenuate MAPK and Akt pathways. S-nitroso-N-acetylpenicillamine (SNAP), [2] S-nitrosoglutathione (GSNO), [3] glucose-SNAP-2, [4] S-nitroso-captopril, [5] DETA-NONOate, [6] sodium nitroprusside, [7] Snitrosocysteine ethyl ester. NO, nitric oxide.…”