Regulation of the <i>Il4</i> Gene Is Independently Controlled by Proximal and Distal 3′ Enhancers in Mast Cells and Basophils

Yagi, Ryouji; Tanaka, Shinya; Motomura, Yasutaka; Kubo, Masato

doi:10.1128/mcb.00631-07

Cited by 29 publications

(37 citation statements)

References 48 publications

(57 reference statements)

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“…Although several cell types, including Th2 cells and basophils, can produce IL-4, each cell type uses distinct cis-regulatory element for the Il4 gene expression (38). Basophils, unlike Th2 cells, do not express Th2 transcription factors GATA3, RBPJκ, or c-Maf (34).…”

Section: Discussionmentioning

confidence: 99%

“…C/EBPα has been shown to directly regulate Il4 gene transcription in basophils, in cooperation with NFAT (34). Although GATA-1 and GATA-2 have been reported to bind to the intronic enhancer of the Il4 gene in mast cells (39), basophils used the HS4 element rather than the intronic enhancer as a lineage-specific Il4 enhancer (38). Thus, the role of GATA-1 and GATA-2 in the Il4 gene regulation in basophils remained uncertain.…”

Section: Discussionmentioning

confidence: 99%

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GATA-1 regulates the generation and function of basophils

Nei¹,

Obata-Ninomiya²,

Tsutsui³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Developmental processes of hematopoietic cells are orchestrated by transcriptional networks. GATA-1, the founding member of the GATA family of transcription factors, has been demonstrated to play crucial roles in the differentiation of erythroid cells, magakaryocytes, eosinophils, and mast cells. However, the role of GATA-1 in basophils remains elusive. Here we show that basophils abundantly express Gata1 mRNAs, and that siRNA-mediated knockdown of Gata1 resulted in impaired production of IL-4 by basophils in response to the stimulation with IgE plus antigens. ΔdblGATA mice that carry the mutated Gata1 promoter and are widely used for functional analysis of eosinophils owing to their selective loss of eosinophils showed a decreased number of basophils with reduced expression of Gata1 mRNAs. The number of basophil progenitors in bone marrow was reduced in these mice, and the generation of basophils from their bone marrow cells in culture with IL-3 or thymic stromal lymphopoietin was impaired. ΔdblGATA basophils responded poorly ex vivo to stimulation with IgE plus antigens compared with wild-type basophils as assessed by degranulation and production of IL-4 and IL-6. Moreover, ΔdblGATA mice showed impaired responses in basophil-mediated protective immunity against intestinal helminth infection. Thus, ΔdblGATA mice showed numerical and functional aberrancy in basophils in addition to the known deficiency of eosinophils. Our findings demonstrate that GATA-1 plays a key role in the generation and function of basophils and underscore the need for careful distinction of the cell lineage responsible for each phenotype observed in ΔdblGATA mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GATA-1 regulates the generation and function of basophils

Nei¹,

Obata-Ninomiya²,

Tsutsui³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…HS4 GFP reporter Tg mice were described previously (20). Mice expressing the human DTR under the control of IE element (for Mas-TRECK) and 39UTR element (for Bas-TRECK) in the Il4 gene locus were generated by a Tg strategy.…”

Section: Micementioning

confidence: 99%

“…The CD4 + T cells (1 3 10 5 cells) were restimulated with OVA (10 mg/ml) for 48 h in the presence of irradiated syngeneic spleen cells (5 3 10 5 cells), and IL-4 production was assessed by ELISA. HS4 GFP reporter Tg mice (20) were injected with OVA (50 mg) and papain (50 mg) in the footpad, and dLNs were harvested at day 4. Frozen sections were prepared for immunohistochemical staining with anti-GFP Alexa Fluor 488 (BD Bioscience), anti-B220-PE (RA3-6B2), anti-Thy1.2-biotin (BD Bioscience), and avidin-Alexa Fluor 647 (Invitrogen, Carlsbad, CA).…”

Section: Papain-induced Il-4 Production and Basophil Migrationmentioning

confidence: 99%

“…In addition, the importance of the myeloid lineage as an innate source of IL-4 was suggested by a series of studies using bicistronic IL-4 reporter (4get) knock-in mice (19). We previously demonstrated that MCs and basophils use different enhancer elements to regulate Il4 gene expression (20). Our data indicated that the intronic enhancer (IE) is a regulatory element for MC, whereas a 39 4-kb fragment that contains the 39 untranslated region (39UTR) and HS4 elements is a specific enhancer for basophils.…”

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confidence: 99%

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Role of Mast Cells and Basophils in IgE Responses and in Allergic Airway Hyperresponsiveness

Sawaguchi

Tanaka

Nakatani

et al. 2012

The Journal of Immunology

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147

153

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We established a diphtheria toxin (DT)-based conditional deletion system using Il4 enhancer elements previously shown to be specific for IL-4 production in mast cells (MCs) or basophils (Mas-TRECK and Bas-TRECK mice). DT treatment of Bas-TRECK mice resulted in specific deletion of basophils, whereas both MCs and basophils were deleted in Mas-TRECK mice. DT-treated Mas-TRECK mice had impaired passive cutaneous anaphylaxis, IgE-mediated passive systemic anaphylaxis, and IgE-mediated chronic allergic inflammation, whereas DT-treated Bas-TRECK mice had impaired IgE-mediated chronic allergic inflammation. Using these mice, we also sought to tease out the role of MCs and basophils in airway hyperresponsiveness (AHR). Although MC deletion resulted in a slight increase in basal Ag-specific IgE levels and significant increases in basal IgE levels, we found that this deletion markedly impaired the AHR effector phase and was accompanied by decreased histamine levels. By contrast, basophil deletion had no effect on the AHR effector phase or on IgE production induced by systemic OVA immunization. Our results, using these newly established Mas-TRECK and Bas-TRECK models, demonstrated an indispensable role for MCs as effector cells in AHR.

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Regulation of IL-4 Expression in Immunity and Diseases

Miaw

2016

Advances in Experimental Medicine and Biology

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IL-4 was first identified as a T cell-derived growth factor for B cells. Studies over the past several decades have markedly expanded our understanding of its cellular sources and function. In addition to T cells, IL-4 is produced by innate lymphocytes, such as NTK cells, and myeloid cells, such as basophils and mast cells. It is a signature cytokine of type 2 immune response but also has a nonimmune function. Its expression is tightly regulated at several levels, including signaling pathways, transcription factors, epigenetic modifications, microRNA, and long noncoding RNA. This chapter will review in detail the molecular mechanism regulating the cell type-specific expression of IL-4 in physiological and pathological type 2 immune responses.

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Regulation of the Il4 Gene Is Independently Controlled by Proximal and Distal 3′ Enhancers in Mast Cells and Basophils

Cited by 29 publications

References 48 publications

GATA-1 regulates the generation and function of basophils

GATA-1 regulates the generation and function of basophils

Role of Mast Cells and Basophils in IgE Responses and in Allergic Airway Hyperresponsiveness

Regulation of IL-4 Expression in Immunity and Diseases

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