TY - JOUR
T1 - Role of increased guanosine triphosphate cyclohydrolase-1 expression and tetrahydrobiopterin levels upon T cell activation
AU - Chen, Wei
AU - Li, Li
AU - Brod, Torben
AU - Saeed, Omar
AU - Thabet, Salim
AU - Jansen, Thomas
AU - Dikalov, Sergey
AU - Weyand, Cornelia
AU - Goronzy, Jorg
AU - Harrison, David G.
PY - 2011/4/22
Y1 - 2011/4/22
N2 - Tetrahydrobiopterin (BH4) 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 BH4 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 BH4 levels. Resting T cells had minimal expression of inducible NOS (NOS2), endothelial NOS (NOS3), and GTPCH-1 protein and nearly undetectable levels of BH4. 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 BH4 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(1mmol/liter) prevented T cell BH4 accumulation, reduced NO production, and increased T cell O-̇2 production, due to both NOS2 and NOS3 uncoupling. GTPCH-1 inhibition also promoted TH2 polarization in memory CD4 cells. Ovalbumin immunization of mice transgenic for an ovalbumin receptor (OT-II mice) confirmed a marked increase in T cell BH4in vivo. These studies identify a previously unidentified consequence of T cell activation, promoting BH4 levels, NO production, and modulating T cell cytokine production.
AB - Tetrahydrobiopterin (BH4) 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 BH4 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 BH4 levels. Resting T cells had minimal expression of inducible NOS (NOS2), endothelial NOS (NOS3), and GTPCH-1 protein and nearly undetectable levels of BH4. 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 BH4 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(1mmol/liter) prevented T cell BH4 accumulation, reduced NO production, and increased T cell O-̇2 production, due to both NOS2 and NOS3 uncoupling. GTPCH-1 inhibition also promoted TH2 polarization in memory CD4 cells. Ovalbumin immunization of mice transgenic for an ovalbumin receptor (OT-II mice) confirmed a marked increase in T cell BH4in vivo. These studies identify a previously unidentified consequence of T cell activation, promoting BH4 levels, NO production, and modulating T cell cytokine production.
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U2 - 10.1074/jbc.M110.191023
DO - 10.1074/jbc.M110.191023
M3 - Article
C2 - 21343293
AN - SCOPUS:79954581861
SN - 0021-9258
VL - 286
SP - 13846
EP - 13851
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 16
ER -