Transcriptional activation of theIL31gene 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.

Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology

“…Studying the promoter region of the IL31 gene Park et al identified IL-4-dependent STAT6 and calcium-dependent NFAT2 (NFATc1) and NFAT1 (NFATc2) binding sites which appear to act synergistically to enhance IL-31 expression in T H 2 lymphocytes and mast cells [125]. These transcription factor binding sites are evolutionary conserved.…”

NFAT1 and JunB Cooperatively Regulate IL-31 Gene Expression in CD4+ T Cells in Health and Disease

“…Therefore, we decided to focus on the synergistic effect between NFAT1 and JunB for IL-31 gene expression. We also tested whether STAT6 could activate the mouse IL-31 promoter because STAT6 was reported as a key transcription factor for enhancing the human IL-31 promoter activity (24). Unlike in the human IL-31 promoter, NFAT2 and STAT6 failed to activate the mouse IL-31 promoter, and NFAT1 alone sufficiently activated the mouse IL-31 promoter in a STAT6-independent manner (Supplemental Fig.…”

“…Genomic sequences spanning the IL-31 gene were analyzed using the Web-based alignment software VISTA browser 2.0 (23). Transcription factor binding sites were identified using the rVISTA 2.0 software (24), which uses matrices of the TRANSFAC database (25). Putative recognition sites for regulatory factors were also identified by searching the JASPAR database (26) and verified from previously reported literature.…”

The Effects of Antigen-Specific IgG1 Antibody for the Pulmonary-Hypertension-Phenotype and B Cells for Inflammation in Mice Exposed to Antigen and Fine Particles from Air Pollution

“…Receptors for IL-13 and IgG are present on these cell types. Signals via signal transducer and activator of transcription 6 (STAT6, IL-13-receptor initiated) and nuclear factor of activated T cells (NFAT, IgG–Fc-receptor initiated) can for example function synergistically for inflammatory cytokine production [78]. Several lines of evidence indicate that NFAT signaling can contribute to the behavioral changes in endothelial cells and smooth muscle cells that cause pulmonary arterial remodeling and constriction then resulting in pulmonary hypertension [17, 79, 80].…”