AICAR suppresses IL-2 expression through inhibition of GSK-3 phosphorylation and NF-AT activation in Jurkat T cells.
We examined the effect of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), the dephosphorylated form of AICA ribotide (also termed "ZMP"), an intermediate of purine biosynthesis, on interleukin (IL)-2 production in T cells. AICAR inhibited IL-2 production in Jurkat T cells and peripheral blood lymphocytes activated with PMA plus ionomycin (PMA/Io) or with monoclonal anti-CD3 plus anti-CD28. Pretreatment with 5'-iodotubercidin, an adenosine kinase inhibitor, enhanced AICAR suppression of IL-2 production, suggesting that AICAR, not ZMP, is responsible for IL-2 suppression. We then showed that AICAR inhibited PMA/Io-induced IL-2 mRNA expression and IL-2 promoter activation. AICAR inhibited DNA binding and transcriptional activation of NF-AT and to a lesser extent AP-1, but not NF-kappaB, in PMA/Io-activated Jurkat cells. Finally, we found that AICAR inhibited PMA/Io-induced phosphorylation of GSK-3 but not phosphorylation of ERK1/2, p38, and JNK. These results suggest that AICAR exerts its immunosuppressive effect in activated Jurkat cells by inhibiting GSK-3 phosphorylation and NF-AT activation.
Jhun
Bong Sook
BS
Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
Oh
Young Taek
YT
Lee
Jung Yeon
JY
Kong
Yoon
Y
Yoon
Kyung-Sik
KS
Kim
Sung Soo
SS
Baik
Hyung Hwan
HH
Ha
Joohun
J
Kang
Insug
I
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D019169:Jurkat Cells; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000819:agonists* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012263:Ribonucleosides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012263:Ribonucleosides; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D038362:Glycogen Synthase Kinase 3