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Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon gamma.

ABSTRACT: Interleukin 12 (IL-12) is a major inducer of interferon gamma (IFN-gamma) and the principal mediator of T helper 1 (Th1) differentiation. To identify IL-12-regulated genes, which might contribute to Th1 differentiation and IFNG regulation, we employed microarray analysis. Surprisingly, a ubiquitously expressed proprotein convertase (PC), furin, was one of the most consistently IL-12-induced genes in T cells, and among PCs was the only one regulated by this cytokine. Furin was preferentially expressed in differentiated Th1 cells in a Stat4-dependent manner. Expression of furin enhanced IFN-gamma secretion, whereas inhibition of furin interfered with IFN-gamma production. Thus, we conclude that IL-12 induction of furin might represent a new aspect of IFN-gamma regulation and control of Th1 differentiation.

SUBMITTER: Pesu M

PROVIDER: S-EPMC1895858 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon gamma.

Pesu Marko M Muul Linda L Kanno Yuka Y O'Shea John J JJ

Blood 20060420 3

Interleukin 12 (IL-12) is a major inducer of interferon gamma (IFN-gamma) and the principal mediator of T helper 1 (Th1) differentiation. To identify IL-12-regulated genes, which might contribute to Th1 differentiation and IFNG regulation, we employed microarray analysis. Surprisingly, a ubiquitously expressed proprotein convertase (PC), furin, was one of the most consistently IL-12-induced genes in T cells, and among PCs was the only one regulated by this cytokine. Furin was preferentially expr ...[more]

PMID: 16627761

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Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T Cells.

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Myeloid cell expressed proprotein convertase FURIN attenuates inflammation.

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Proprotein convertase furin regulates apoptosis and proliferation of granulosa cells in the rat ovary.

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T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development.

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T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance.

Project description:Furin is one of seven proprotein convertase family members that promote proteolytic maturation of proproteins. It is induced in activated T cells and is reported to process a variety of substrates including the anti-inflammatory cytokine transforming growth factor (TGF)-beta1 (refs 2-4), but the non-redundant functions of furin versus other proprotein convertases in T cells are unclear. Here we show that conditional deletion of furin in T cells allowed for normal T-cell development but impaired the function of regulatory and effector T cells, which produced less TGF-beta1. Furin-deficient T regulatory (Treg) cells were less protective in a T-cell transfer colitis model and failed to induce Foxp3 in normal T cells. Additionally, furin-deficient effector cells were inherently over-active and were resistant to suppressive activity of wild-type Treg cells. Thus, our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its non-redundant, essential function in regulating TGF-beta1 production. Targeting furin has emerged as a strategy in malignant and infectious disease. Our results suggest that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance.

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T cell-expressed proprotein convertase furin is essential for maintenance of peripheral tolerance

Project description:Furin is a proprotein convertase induced in activated T cells, reported to processes the anti-inflammatory cytokine TGFb-1. Herein, we show that conditional deletion of furin in T cells allowed for normal T cell development but impaired the function of regulatory T cells and effector cells, which produced less TGFb-1. Furin-deficient Treg cells, were less protective in a T cell transfer colitis model and failed to induce Foxp3 in normal T cells. Furin-deficient effector cells were inherently overly active and were resistant to suppressive activity of wild-type Tregs. Thus, our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its nonredundant, essential function in regulating TGFb-1 production. Targeting furin has emerged as a strategy in malignant and infectious disease. The current work suggests that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance.

2008-06-26 | GSE11884 | GEO

The proprotein convertase furin regulates the development of thymic epithelial cells to ensure central immune tolerance.

Project description:The generation of mature T cells and establishment of central tolerance is predominantly orchestrated by thymic epithelial cells (TECs). Proprotein convertases are responsible for the proteolysis of proproteins into their mature bioactive counterparts. Here, we found that Furin, a member of the subtilisin/kexin-like PCs family, is highly expressed in TECs compared with other members of this family. TEC-specific deletion of Furin caused severe thymic atrophy and predominantly reduced the number of medullary TECs and thymic tuft cells, and to a less degree, cortical TECs. Furin deletion attenuated the proliferation of TECs, impaired thymopoiesis, and led to autoimmune disorders in mice. Furin promotes the development of TECs via cleavage of proIGF1 receptor and pro-Insulin receptor and the activation of downstream ERK/MAPK and Akt signaling pathways. Thus, this study uncovered the role of furin in TEC development and function and highlighted the importance of post-translational modification of immature proproteins in TEC biology.

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The proprotein convertase furin is required for trophoblast syncytialization.

Project description:The multinucleated syncytial trophoblast, which forms the outermost layer of the placenta and serves multiple functions, is differentiated from and maintained by cytotrophoblast cell fusion. Deficiencies in syncytial trophoblast differentiation or maintenance likely contribute to intrauterine growth restriction and pre-eclampsia, two common gestational diseases. The cellular and molecular mechanisms governing trophoblast syncytialization are poorly understood. We report here that the proprotein convertase furin is highly expressed in syncytial trophoblast in the first trimester human placentas, and expression of furin in the syncytiotrophoblast is significantly lower in the placentas from pre-eclamptic patients as compared with their gestational age-matched control placentas. Using multiple experimental models including induced fusion of choriocarcinoma BeWo cells and spontaneous fusion of primary cultured cytotrophoblast cells or placental explants, we demonstrate that cytotrophoblast cell fusion and syncytialization are accompanied by furin expression. Furin-specific siRNAs or inhibitors inhibit cell fusion in BeWo cells, as well as trophoblast syncytialization in human placental explants. Furthermore, type 1 IGF receptor (IGF1R) is indicated in this study as a substrate of furin, and processing of IGF1R by furin is an essential mechanism for syncytialization. Finally, using lentivirus-mediated RNAi targeting to mouse trophectoderm, we demonstrate that furin function is required for the development of syncytiotrophoblast structure in the labyrinth layer, as well as for normal embryonic development.

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