Critical role of the endogenous interferon ligand–receptors in type I and type <scp>II</scp> interferons response

Lasfar, Ahmed; Cook, Jeffry R.; Solal, Karine A. Cohen; Reuhl, Kenneth R.; Langer, Jerome A.; Laskin, Debra L.

doi:10.1111/imm.12273

Cited by 18 publications

(11 citation statements)

References 60 publications

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“…To sustain the expression of inflammation genes, type I IFNs can act in an autocrine loop by binding a heterodimeric complex of the IFNAR1 and IFNAR2 on the cell surface (29). IFNAR1/2 activation initiates a signaling cascade through the Janus kinase and signal transducer and activator of transcription pathway that induces the transcription of hundreds of ISGs (30, 31).…”

Section: Resultsmentioning

confidence: 99%

HIPK2 is necessary for type I interferon–mediated antiviral immunity

et al. 2019

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Precise control of interferons (IFNs) is crucial to maintain immune homeostasis. Here, we demonstrated that homeodomain-interacting protein kinase 2 (HIPK2) was required for the production of type I IFNs in response to RNA virus infection. HIPK2 deficiency markedly impaired IFN production in macrophages after vesicular stomatitis virus (VSV) infection, and HIPK2-deficient mice were more susceptible to lethal VSV disease than were wild-type mice. After VSV infection, HIPK2 was cleaved by active caspases, which released a hyperactive, N-terminal fragment that translocated to the nucleus and further augmented antiviral responses. In part, HIPK2 interacted with ELF4 and promoted its phosphorylation at Ser369, which enabled Ifn-β transcription. In addition, HIPK2 production was stimulated by type I IFNs to further enhance antiviral immunity. These data suggest that the kinase activity and nuclear localization of HIPK2 are essential for the production of type I IFNs.

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Section: Resultsmentioning

confidence: 99%

HIPK2 is necessary for type I interferon–mediated antiviral immunity

et al. 2019

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“…Unlike IFN-γ, which signals through its unique receptor, all type I interferons signal through the IFN-α receptor 1 (IFNAR1) and IFN-α receptor 2 (IFNAR2) [ 1 ]. Although signaling occurs through different receptors, lack of IFNAR can lead to a diminished IFN-γ signaling pathway, implicating IFNAR in regulation of IFN-γ responsiveness [ 31 ]. To address whether the lack of STAT1 induction in TL-1 cells is specific to IFN-γ or a result of diminished IFNAR-mediated signaling, we assessed the ability of TL-1 cells to respond to IFN-β.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, we demonstrate that the lack of IFN-γ responsiveness is not due to defects in the type I interferon signaling pathway ( Fig 4 ). Deficiency in the type I interferon receptors IFNAR1 and IFNAR2 has been shown to dampen IFN-γ signaling [ 31 ]. However, we found that TL-1 cells robustly induce p-STAT1 in response to IFN-β treatment ( Fig 4 ).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of the IFN-γ-STAT1 signaling pathway in a cell line model of large granular lymphocyte leukemia

et al. 2018

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T cell large granular lymphocyte leukemia (T-LGLL) is a rare incurable disease that is characterized by defective apoptosis of cytotoxic CD8+ T cells. Chronic activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway is a hallmark of T-LGLL. One manifestation is the constitutive phosphorylation of tyrosine 701 of STAT1 (p-STAT1). T-LGLL patients also exhibit elevated serum levels of the STAT1 activator, interferon-γ (IFN-γ), thus contributing to an inflammatory environment. In normal cells, IFN-γ production is tightly controlled through induction of IFN-γ negative regulators. However, in T-LGLL, IFN-γ signaling lacks this negative feedback mechanism as evidenced by excessive IFN-γ production and decreased levels of suppressors of cytokine signaling 1 (SOCS1), a negative regulator of IFN-γ. Here we characterize the IFN-γ-STAT1 pathway in TL-1 cells, a cell line model of T-LGLL. TL-1 cells exhibited lower IFN-γ receptor protein and mRNA expression compared to an IFN-γ responsive cell line. Furthermore, IFN-γ treatment did not induce JAK2 or STAT1 activation or transcription of IFN-γ-inducible gene targets. However, IFN-β induced p-STAT1 and subsequent STAT1 gene transcription, demonstrating a specific IFN-γ signaling defect in TL-1 cells. We utilized siRNA targeting of STAT1, STAT3, and STAT5b to probe their role in IL-2-mediated IFN-γ regulation. These studies identified STAT5b as a positive regulator of IFN-γ production. We also characterized the relationship between STAT1, STAT3, and STAT5b proteins. Surprisingly, p-STAT1 was positively correlated with STAT3 levels while STAT5b suppressed the activation of both STAT1 and STAT3. Taken together, these results suggest that the dysregulation of the IFN-γ-STAT1 signaling pathway in TL-1 cells likely results from low levels of the IFN-γ receptor. The resulting inability to induce negative feedback regulators explains the observed elevated IL-2 driven IFN-γ production. Future work will elucidate the best way to target this pathway, with the ultimate goal to find a better therapeutic for T-LGLL.

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“…In the current study, increased mRNA expression levels of IFNGR 1 and IFNGR 2 were observed in the pituitary following treatment with IFN-γ. The IFN-γ ligand is a dimmer and binds to a heterodimer receptor, which activates the signal transduction cascades and results in the dimerization of the signal transducers and activators of gene transcription [ 7 , 8 , 47 ]. In our research, the combination of endogenous IFN-γ ligand and the pre-assembled up-regulated receptor complex activated the relevant signaling pathways and led to increased FSH-β expression at the transcription level, promoting the synthesis and secretion of FSH.…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ acts as a regulator in the trade-off between phagocytosis and production performance in dwarf chickens

Yuan

Liu

Zhao

et al. 2018

J Animal Sci Biotechnol

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BackgroundInterferon-γ (IFN-γ) is critical for innate and adaptive immunity against viral and bacterial infections. IFN-γ reportedly affects the phagocytic ability of monocytes and macrophages as well as regulates pituitary function in humans and mice. The present study analyzed the impact of IFN-γ on monocyte and macrophage phagocytosis, production performance, and pituitary function in vivo and in vitro (in dwarf chickens). IFN-γ was injected into dwarf chickens through a vein, and then, the laying rate, average egg weight, and levels of follicle-stimulating hormone (FSH) and IFN-γ were measured in treatment and control groups. For the in vitro experiment, the pituitary tissues were supplemented with IFN-γ, and the mRNA expression levels of follicle-stimulating hormone beta subunit (FSH-β), interferon gamma receptor 1 (IFNGR1), and interferon gamma receptor 2 (IFNGR2) in the pituitary were assessed.ResultsMonocyte and macrophage phagocytosis product (PP) was decreased by IFN-γ treatment in a dose-dependent manner in vitro. In the in vivo experiment, the level of IFN-γ in the treatment group was higher than that in the control group at 7 d (P < 0.05), 14 d (P < 0.01), and 21 d (P < 0.01) post-injection. Compared with the control group, monocyte and macrophage PP was lower in the treatment group after injection (P < 0.01). The laying rate was higher in the treatment group than in the control group at 2 and 3 wk post-injection (P < 0.05). There was a significant difference between the treatment and control groups in the levels of FSH at 1, 3, 7, and 14 d post-injection (P < 0.01). In the in vitro experiment, increased mRNA expression levels of FSH-β, IFNGR1, and IFNGR2 were observed in the treatment group after stimulation with 100 U/mL IFN-γ for 24 h compared to those in the control group (P < 0.05).ConclusionsIFN-γ inhibited the phagocytosis of monocytes and macrophages; up-regulated the mRNA expression levels of the FSH-β, IFNGR1, and IFNGR2; enhanced the secretion of FSH; and improved the laying rate. IFN-γ might be an important regulator in the trade-off between the immune effect and production performance in dwarf chickens.

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Critical role of the endogenous interferon ligand–receptors in type I and type II interferons response

Cited by 18 publications

References 60 publications

HIPK2 is necessary for type I interferon–mediated antiviral immunity

HIPK2 is necessary for type I interferon–mediated antiviral immunity

Dysregulation of the IFN-γ-STAT1 signaling pathway in a cell line model of large granular lymphocyte leukemia

Interferon-γ acts as a regulator in the trade-off between phagocytosis and production performance in dwarf chickens

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