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

Abstract

IL-31 is a key mediator of itching in atopic dermatitis (AD) and is preferentially produced by activated CD4+ T cells and Th2 cells. Although pathophysiological functions of IL-31 have been suggested in diverse immune disorders, the molecular events underlying IL-31 gene regulation are still unclear. In this study we identified the transcription start site and functional promoter involved in IL-31 gene regulation in mouse CD4+ T cells. TCR stimulation–dependent IL-31 expression was found to be closely linked with in vivo binding of NFAT1 and JunB to the IL-31 promoter. Although NFAT1 alone enhanced IL-31 promoter activity, it was further enhanced in the presence of JunB. Conversely, knockdown of either NFAT1 or JunB resulted in reduced IL-31 expression. NFAT1-deficient CD4+ T cells showed a significant defect in IL-31 expression compared with wild-type CD4+ T cells. In agreement with these findings, mice subjected to atopic conditions showed much higher levels of IL-31, which were closely correlated with a significant increase in the number of infiltrated NFAT1+CD4+ T cells into the AD ears. Amelioration of AD progression by cyclosporin A treatment was well correlated with downregulation of IL-31 expressions in CD4+ T cells and total ear residual cells. In summary, our results suggest a functional cooperation between NFAT1 and JunB in mediating IL-31 gene expression in CD4+ T cells and indicate that interference with this interaction or their activity has the potential of reducing IL-31–mediated AD symptoms.

Identification of Novel Nuclear Factor of Activated T Cell (NFAT)-associated Proteins in T Cells

“…Most of these constitute newly identified partners of NFAT proteins and link NFAT proteins to several other transcription factors, to the SWI/SNF complex, or to the DNA-damage response. Additionally, our analysis confirmed several NFAT interactions that were previously identified by others, such as AP1 proteins, the co-activator p300, 14-3-3 proteins and known NFAT kinases (15,19,23,28,42).…”

“…wild type) NFAT proteins, BirA and BT-GFP or BirA and BT-histone H4, by an analogous strategy. We confirmed the potential of our NFAT-BT fusion proteins to study NFAT protein interactions by the specific co-purification of the known NFAT protein interactors p300, c-JUN, JUNB, and c-FOS along with the captured NFATc2-BT (data not shown) (28,31,42).…”

Possible Antipruritic Mechanism of Cyclosporine A in Atopic Dermatitis

“…In addition, NK1R-immunoreactive fibres have also been shown to increase in the lesional skin of patients with AD and atopic NC/Nga mice (33). Taken together, our data suggested that CsA partly attenuates pruritus in AD via inhibitory effects on gene expression of both IL-31RA and NK1R in the DRG, in addition to reduced production of itch-related ligands, such as IL-31 and TSLP caused by calcineurin blockade (5,7,34). In fact, although TSLP levels did not reduce by CsA treatment, IL-31 + cells in the dermis were lower in the 5 mg/kg CsA-treated group than in the others (Fig.…”

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

“…These transcription factor binding sites are evolutionary conserved. Recently, the STAT6/ NFAT responsiveness of the IL31 promoter has been confirmed [126,127] and expanded by two newly identified response elements: (1) binding of JunB to conserved AP-1 binding sites which cooperate with NFAT1 to induce IL-31 expression in T cells [127] and (2) a novel NF-kB binding element that mediates the enhancing effect of IL-33 on IL-4/STAT6-induced IL-31 expression in human T H 2 cells [126]. Therefore, IL-31 is not a T H 2 cytokine in the classical sense, but induced in many cell types during allergic responses in which IL-4 is present [128].…”