Delayed Lymphoid Repopulation with Defects in IL-4–Driven Responses Produced by Inactivation of NF-ATc

Ranger, Ann; Hodge, Martin R.; Gravallese, Ellen M.; Oukka, Mohammed; Davidson, Laurie A.; Alt, Frederick W.; Brousse, Fabienne Charles de la; Hoey, Timothy; Grusby, Michael J.; Glimcher, Laurie H.

doi:10.1016/s1074-7613(00)80465-3

Cited by 276 publications

(202 citation statements)

References 44 publications

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“…Strong synergy was also Whole cell extracts were analyzed by immunoblotting with an anti-NFAT2 antibody (mAb 7A6) to assess protein dephosphorylation. Note that this genetic disruption does not result in a completely null phenotype for NFAT2; as described in (39,61), faint bands corresponding to a truncated form of NFAT2 unable to bind DNA are still apparent in the NFAT2Ϫ/Ϫ ESMC extracts. WB, Western blot.…”

Section: Impaired Cooperation Of Nfat2 With Gata Proteins In Mastmentioning

confidence: 72%

Role of NFAT Proteins in IL13 Gene Transcription in Mast Cells

Monticelli

Solymar

Rao

2004

Journal of Biological Chemistry

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Th2 and mast cells are participants in the asthmatic response to allergens, and both cell types produce the cytokines interleukin (IL)-4 and IL-13. IL-13 in particular is both necessary and sufficient for experimental models of asthma. The transcription factor NFAT plays a central role in cytokine transcriptional regulation in both cell types. Here, we analyze the molecular basis of IL13 gene transcription in Th2 and mast cells. We show that NFAT1 is the major NFAT protein involved in regulating IL13 transcription in mast cells. Although NFAT2 is correctly expressed and regulated in mast cells, it does not contribute to IL13 gene transcription as shown by analysis of cells lacking NFAT2 and cells expressing a constitutively active version of NFAT2. The difference between NFAT1 and NFAT2 appears to be due to a preferential synergistic interaction of NFAT1 with GATA proteins at the IL13 promoter. We suggest that mast cells lack a co-activator protein that stabilizes the binding of NFAT2 to the IL13 promoter by interacting either with NFAT2 itself or with a DNA-bound complex of NFAT2 and GATA proteins.Th2 cells and mast cells are both central players in the pathophysiology of asthma (1). Th2 cells are characterized by the ability to produce a specific panel of cytokines, IL-4, 1 IL-5, and IL-13. These cytokines are also produced by mast cells (2, 3), even though mast cells and Th2 cells derive from two different compartments of the immune system (myeloid and lymphoid respectively). Expression of Th2-type cytokines is strongly associated with asthma; this is demonstrated by the fact that human asthma has been linked to a region of chromosome 5q containing the IL4, IL5, and IL13 genes (4). Although IL-4 and IL-5 have been implicated in asthma, IL-13 is now thought to be especially critical. In animal models of allergic asthma, blockade of IL-13 markedly inhibited allergeninduced airway hyperresponsivness, mucus production, and eosinophilia. Furthermore, IL-13 delivery to the airways was able to cause all of these effects. IL-13 is thus both necessary and sufficient for experimental models of asthma (5, 6).In Th2 cells, production of the cytokines IL-4, IL-5, and IL-13 is controlled by cooperation between two families of transcription factors, the GATA and NFAT families (3, 7-9). The calcium-regulated transcription factor NFAT consists of four family members, three of which (NFAT1 (p, c2), NFAT2 (c, c1), NFAT4 (x, c3)) are expressed in both cell types (3, 9 -11). Targeted disruption of the genes encoding individual NFAT family members suggests that there are cell type-and gene-specific differences in their ability to regulate gene transcription in activated cells (11,12). The GATA family of transcription factors is also essential for IL-4, IL-5, and IL-13 by Th2 cells, as shown by increased and decreased expression of these cytokines in transgenic mice overexpressing wild-type GATA3 (7) and a dominant-negative version of GATA3 (8) respectively. In addition to playing a role in Th2 cytokine expression, GATA3 is importa...

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Section: Impaired Cooperation Of Nfat2 With Gata Proteins In Mastmentioning

confidence: 72%

Role of NFAT Proteins in IL13 Gene Transcription in Mast Cells

Monticelli

Solymar

Rao

2004

Journal of Biological Chemistry

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“…It has been well characterized that redundancy within the NFAT family exists. In general, knocking out one NFAT protein results only in a mild phenotype, whereas knocking out two or more members leads to striking defects (45)(46)(47)(48)(49)(50)(51)(52)(53). The phenotypes of these mice seem to indicate that although NFAT1 and NFAT2 proteins regulate the expression of activation-induced genes, it is NFAT1 and NFAT4 that might be specifically involved in controlling cellular programs that lead to the negative regulation of T cell responses.…”

Section: Retroviral Infection Of Primary T Cellsmentioning

confidence: 99%

Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance

Soto-Nieves¹,

Puga²,

Abe³

et al. 2009

J Cell Biol

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“…NFATc1-deficient mice are embryonic lethal due to a defect in cardiac development (18,19). NFATc1-deficient T cells show reduced proliferation, activation, and IL-4 production (20,21). NFATc2-deficient T cells exhibit hyperproliferation and dysregulated IL-4 gene expression and enhanced Th2 immune response (22)(23)(24)(25)(26).…”

Section: Inhibition Of Nfat Specifically In T Cells Prevents Allergicmentioning

confidence: 99%

Inhibition of NFAT Specifically in T Cells Prevents Allergic Pulmonary Inflammation

Diehl¹,

Krahl²,

Rinaldi

et al. 2004

The Journal of Immunology

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NFAT is a family of transcription factors important in the regulation of cytokine genes and is widely expressed in different lymphoid and nonlymphoid tissues. Consequently, the role of NFAT in CD4+ T cells during an in vivo immune response is not completely clear. In this study, we use transgenic mice expressing a dominant negative NFAT mutant exclusively in T cells to address the role of NFAT in T cells during a Th2 immune response in a model of allergic airway inflammation. We have observed that inhibition of NFAT in T cells results in a reduction of Ag-specific Th2 Ab levels and IL-4 production by CD4+ T cells. The accumulation of eosinophils in the bronchoalveolar lavage is delayed in dominant negative NFAT-transgenic mice. These mice are also more resistant to the development of lung pathology in response to allergen exposure. We, therefore, conclude that activation of NFAT in CD4+ T cells is required for the development of a Th2 immune response in vivo and allergic airway inflammation.

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Delayed Lymphoid Repopulation with Defects in IL-4–Driven Responses Produced by Inactivation of NF-ATc

Cited by 276 publications

References 44 publications

Role of NFAT Proteins in IL13 Gene Transcription in Mast Cells

Role of NFAT Proteins in IL13 Gene Transcription in Mast Cells

Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance

Inhibition of NFAT Specifically in T Cells Prevents Allergic Pulmonary Inflammation

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