Tributylhexadecylphosphonium bromide, a novel nuclear factor of activated T cells signaling inhibitor, blocks interleukin-2 induction associated with inhibition of p70 ribosomal protein S6 kinase phosphorylation.
Transcriptional factors of the nuclear factor of activated T cells (NFAT) family are involved in T cell signaling. Many NFAT signaling inhibitors, such as cyclosporin A (CsA) and tacrolimus, abrogate dephosphorylation of NFAT proteins by inhibiting calcineurin activity. In pursuit of a novel type of NFAT signaling inhibitor, we screened our chemical library using the NFAT-dependent reporter assay and identified tributylhexadecylphosphonium bromide (THPB) as a selective NFAT signaling inhibitor. THPB inhibited NFAT-dependent reporter activity, and the induction of interleukin-2 (IL-2) at both mRNA and protein levels by calcium stimulation. Moreover, THPB had an additive effect on the inhibition of IL-2 induction with CsA. Unlike CsA, THPB did not affect dephosphorylation of NFAT1, but suppressed phosphorylation of p70 ribosomal protein S6 kinase (p70S6K). These results suggest that THPB may be a novel type of NFAT signaling inhibitor that acts in association with inhibition of p70S6K phosphorylation.
Graduate School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Hiroshi
H
Umehara
Akira
A
Asai
D002118:Calcium / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009943:Organophosphorus Compounds; D012333:RNA, Messenger; C575594:tributylhexadecylphosphonium bromide; D016572:Cyclosporine; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D002118:Calcium