title: Transcriptional activation of the IL31 gene by NFAT and STAT6.
abstract: IL-31, a newly identified member of the IL-6 cytokine family, is involved in many pathological conditions, including atopic dermatitis and pruritis. In this study, we investigated how expression of IL-31 is regulated in T cells and mast cells. We observed that expression of IL-31 required a calcium signal and was dependent on the calcineurin-NFAT signaling pathway. Moreover, we found that IL-31 promoter contains a positive regulatory region that mediates calcium- and IL-4-dependent induction of the IL-31 gene and demonstrated that a change into an open chromatin conformation occurs in this region after stimulation with calcium and IL-4. Whereas IL-4 responsiveness required STAT6 binding sites, calcium responsiveness of IL-31 promoter required NFAT binding sites that bind NFATc1 and NFATc2 in vitro and in vivo. The induction of IL-31 promoter activity was impaired when these sites were mutated but was enhanced by CA-NFATc1 or STAT6 proteins and further increased synergistically by combinations of both proteins. Furthermore, the importance of STAT6 proteins was indicated by impaired, IL-4-mediated induction of IL-31 in STAT6-diminished Jurkat cells. Thus, our data demonstrate that calcium and IL-4 signals are required to mediate induction of IL-31 in Th2 cells and mast cells and that this induction appears to result from specific binding of NFAT and STAT6 proteins.
authors: Department of Environmental Medical Biology, Institute of Tropical Medicine, and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors: Keunhee
authors: K
authors: Park
authors: Joo-Hong
authors: JH
authors: Park
authors: Wook-Jin
authors: WJ
authors: Yang
authors: Jong-Joo
authors: JJ
authors: Lee
authors: Min-Ji
authors: MJ
authors: Song
authors: Hyoung-Pyo
authors: HP
authors: Kim
mesh_terms: D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000502:physiology; D004140:Dinitrophenols / Q000494:pharmacology; D057809:HEK293 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics*; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D050800:STAT6 Transcription Factor / Q000502:physiology*; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D012709:Serum Albumin / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D004140:Dinitrophenols; C502187:IL31 protein, human; D007378:Interleukins; D050778:NFATC Transcription Factors; D011993:Recombinant Fusion Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D012709:Serum Albumin; C494100:Stat6 protein, mouse; C058064:dinitrophenyl-human serum albumin conjugate; C502588:interleukin-31, mouse; C570835:interleukin-31, rat; D015847:Interleukin-4; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium