| Role of increased guanosine triphosphate cyclohydrolase-1 expression and tetrahydrobiopterin levels upon T cell activation. | |
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MedLine Citation:
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PMID: 21343293 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Tetrahydrobiopterin (BH(4)) is an essential co-factor for the nitric-oxide (NO) synthases, and in its absence these enzymes produce superoxide (O(2)(·-)) rather than NO. The rate-limiting enzyme for BH(4) production is guanosine triphosphate cyclohydrolase-1 (GTPCH-1). Because endogenously produced NO affects T cell function, we sought to determine whether antigen stimulation affected T cell GTPCH-1 expression and ultimately BH(4) levels. Resting T cells had minimal expression of inducible NOS (NOS2), endothelial NOS (NOS3), and GTPCH-1 protein and nearly undetectable levels of BH(4). Anti-CD3 stimulation of T cells robustly stimulated the coordinated expression of NOS2, NOS3, and GTPCH-1 and markedly increased both GTPCH-1 activity and T cell BH(4) levels. The newly expressed GTPCH-1 was phosphorylated on serine 72 and pharmacological inhibition of casein kinase II reduced GTPCH-1 phosphorylation and blunted the increase in T cell BH(4). Inhibition of GTPCH-1 with diaminohydroxypyrimidine (1 mmol/liter) prevented T cell BH(4) accumulation, reduced NO production, and increased T cell O(2)(·-) production, due to both NOS2 and NOS3 uncoupling. GTPCH-1 inhibition also promoted TH(2) polarization in memory CD4 cells. Ovalbumin immunization of mice transgenic for an ovalbumin receptor (OT-II mice) confirmed a marked increase in T cell BH(4) in vivo. These studies identify a previously unidentified consequence of T cell activation, promoting BH(4) levels, NO production, and modulating T cell cytokine production. |
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Authors:
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Wei Chen; Li Li; Torben Brod; Omar Saeed; Salim Thabet; Thomas Jansen; Sergey Dikalov; Cornelia Weyand; Jorg Goronzy; David G Harrison |
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Publication Detail:
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Type: Journal Article Date: 2011-02-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-18 Completed Date: 2011-06-28 Revised Date: 2012-09-19 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 13846-51 Citation Subset: IM |
Affiliation:
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Cardiology Division and Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens, CD3 / biosynthesis Biopterin / analogs & derivatives*, biosynthesis, metabolism Cytokines / biosynthesis GTP Cyclohydrolase / metabolism* Gene Expression Regulation, Enzymologic* Humans Immunologic Memory Mice Mice, Inbred C57BL Mice, Transgenic Ovalbumin / chemistry Oxygen / chemistry Phosphorylation T-Lymphocytes / cytology, enzymology* |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD3; 0/Cytokines; 17528-72-2/5,6,7,8-tetrahydrobiopterin; 22150-76-1/Biopterin; 7782-44-7/Oxygen; 9006-59-1/Ovalbumin; EC 3.5.4.16/GTP Cyclohydrolase |
| Comments/Corrections | |
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