Document Detail

Role of increased guanosine triphosphate cyclohydrolase-1 expression and tetrahydrobiopterin levels upon T cell activation.
MedLine Citation:
PMID:  21343293     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article     Date:  2011-02-22
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-04-18     Completed Date:  2011-06-28     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13846-51     Citation Subset:  IM    
Cardiology Division and Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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MeSH Terms
Antigens, CD3 / biosynthesis
Biopterin / analogs & derivatives*,  biosynthesis,  metabolism
Cytokines / biosynthesis
GTP Cyclohydrolase / metabolism*
Gene Expression Regulation, Enzymologic*
Immunologic Memory
Mice, Inbred C57BL
Mice, Transgenic
Ovalbumin / chemistry
Oxygen / chemistry
T-Lymphocytes / cytology,  enzymology*
Reg. No./Substance:
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 Cyclohydrolase

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