Mitochondrial adenine nucleotide translocator 3 is regulated by IL-4 and IFN-gamma via STAT-dependent pathways.
IL-4 and IFN-gamma are prototypical Th2 and Th1 cytokines, respectively. They reciprocally regulate a number of genes involved in Th1 vs Th2 immune balance. Using DD-PCR analysis, adenine nucleotide translocase (ANT) 3, an enzyme which exchanges ATP and ADP through mitochondrial membrane, has been identified as a novel target counter-regulated by IL-4 and IFN-gamma. We have observed that IL-4 and IFN-gamma each up-regulates ANT3 in T cells both at mRNA and protein levels, while cotreatment of IL-4 and IFN-gamma counter-regulates ANT3 expression. In contrast, other isoforms of ANT were not affected by IL-4 or IFN-gamma. Emplyoing transfection and overexpression of STAT6 and STAT1 in STAT-deficient cells, we demonstrate that induction of ANT3 by IL-4 and IFN-gamma proceeds via pathways involving STAT6 and STAT1, respectively. Furthermore, regulation of ANT3 expression by IL-4 and IFN-gamma correlated with the modulation T cell survival by these cytokines from dex-induced apoptosis. Considering the critical role of mitochondrial ANTs in energy metabolism and apoptosis, ANT3 regulation by IL-4 and IFN-gamma may have a functional implication in cytokine-mediated T cell survival.
Jang
Ji-Young
JY
Department of Biological Science and Institute for Basic Science, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Lee
Choong-Eun
CE
D033781:Adenine Nucleotide Translocator 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*
D033781:Adenine Nucleotide Translocator 3; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma