IFN-γ Suppresses STAT6 Phosphorylation by Inhibiting Its Recruitment to the IL-4 Receptor

Huang, Zan; Xin, Junping; Coleman, John M.; Huang, Hua

doi:10.4049/jimmunol.174.3.1332

Cited by 27 publications

(48 citation statements)

References 39 publications

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“…The data indicate that Delta selectively suppresses the positive effects of the IL-4 signaling pathway on Th2 cell development. Several molecules, such as ICOS-L and IFN-␥, have been shown to affect IL-4 responsiveness during Th polarization by regulating STAT6 phosphorylation (34,35). However, we have not been able to show that Delta inhibits STAT6 phosphorylation in Th cells in response to IL-4 (data not shown).…”

Section: Discussioncontrasting

confidence: 43%

Suppression of Th2 Cell Development by Notch Ligands Delta1 and Delta4

Sun

Krawczyk

Pearce

2008

The Journal of Immunology

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Notch signaling plays important roles in Th cell activation. We show that in response to TLR ligation, dendritic cells up-regulate expression of Notch ligands Delta1 and Delta4 via a MyD88-dependent pathway. Expression of Delta1 or Delta4 by dendritic cells enhanced their ability to activate naive Th cells and promote Th1 cell development, and allowed them to strongly inhibit Th2 cell development. Promotion of Th1 cell development was dependent on IFN-γ and T-bet expression by responding Th cells. However, the inhibition of Th2 cell development occurred independently of IFN-γ or T-bet, and resulted from a block in IL-4-initiated commitment to the Th2 lineage. The promotion of Th1 cell development by Delta is not a reflection of the delivery of pro-Th1 instructional signal, but rather it is the result of a block in the downstream effects initiated by IL-4 signaling.

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Section: Discussioncontrasting

confidence: 43%

Suppression of Th2 Cell Development by Notch Ligands Delta1 and Delta4

Sun

Krawczyk

Pearce

2008

The Journal of Immunology

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Section: Ifn-a Suppresses Nuclear Translocation Of Py-stat6 In B Cellsmentioning

confidence: 61%

“…S1-B and S1-C). This response has a thread connection with the previous reports that IFN-g suppresses STAT6 phosphorylation in various cell types to downregulate IL-4-mediated biological response [22,23,34].In the case of IFN-a, the increased cytoplasmic levels of pY-STAT6 were maintained up to 8 h post-treatment, indicating that cytosolic retention of pY-STAT6 is not a transient but a sustained inhibitory mechanism of IFN-a action on IL-4 signaling (Fig. S2).…”

mentioning

confidence: 67%

“…For example, type I and type II IFNs both inhibit the IL-4-induced STAT6 activation in human monocytes to suppress IL-4-inducible gene expression [22]. In polarized Th1 cells, IFN-g may suppress phosphorylation of STAT6 by inhibiting its recruitment to the IL-4R [23]. As compared to IFN-g, the effects of IFN-a on the IL-4 signaling pathway have been studied in limited cell systems, which indicated rather a complex regulation involving both inhibition and promotion of the STAT6-mediated IL-4 response by IFN-a [22,24].…”

Section: Introductionmentioning

confidence: 99%

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Counter‐regulation mechanism of IL‐4 and IFN‐α signal transduction through cytosolic retention of the pY‐STAT6:pY‐STAT2:p48 complex

Kim¹,

Lee²

2010

Eur J Immunol

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IFN-a and IL-4 induce Th1 and Th2 responses, respectively, and often display antagonistic actions against each other. To elucidate the molecular mechanism of counter-regulation, we have investigated the signal interception by IFN-a and IL-4, employing a human B-cell line Ramos, sensitive to both cytokines. In these cells, IFN-a effectively inhibited IL-4-induced Fc epsilon receptor II (CD23) expression, whereas IL-4 suppressed IFN-amediated IRF7 expression. The counter-regulatory action by IL-4 and IFN-a proceeded with a delayed kinetics requiring 4 h. Notably, IFN-a did not affect the IL-4-induced tyrosine phosphorylation of STAT6, but induced a time-dependent cytoplasmic accumulation of phosphotyrosine(pY)-STAT6 and a corresponding decrease in nuclear pY-STAT6. By confocal analysis and co-immunoprecipitation assays, we demonstrated the colocalization and molecular interaction of IL-4-induced pY-STAT6 with IFN-a-induced pY-STAT2:p48 in the cytosol. In addition, the over-expression of STAT2 or STAT6 induced the concomitant cytosolic accumulation of pY-STAT6 or pY-STAT2, leading to the suppression of IL-4-induced CD23 or IFN-a-induced IRF7 gene expression, respectively. Our data suggest that the signals ensued by IFN-a and IL-4 induce cytoplasmic sequestration of IL-4-activated STAT6 and IFN-a-activated STAT2:p48 in B cells through the formation of pY-STAT6:pY-STAT2:p48 complex, which provides a novel mechanism by which IFN-a and IL-4 cross-regulate their signaling into the nucleus.Keywords: Counter-regulation . Cytosolic retention . IFN-a signaling . IL-4 signaling pY-STAT6:pY-STAT2:p48 complex Supporting Information available online IntroductionIn the innate and the adaptive immune system, cytokines act as key regulators for the activation, proliferation, differentiation, development, and death of immune cells [1,2]. IL-4 is an immunomodulatory cytokine secreted by activated Th2 lymphocytes, basophils, and mast cells [3]. Its pleiotropic functions include the differentiation of Th2 cells, B-cell activation, immunoglobulin isotype switching, the inhibition of Th1 differentiation, and the development of allergic diseases. In hematopoietic cells, responses to IL-4 are mediated by the receptor complex composed of IL-4 receptor (IL-4R) a and common g-chain (gc). Once these receptor chains are heterodimerized upon IL-4 binding, the receptor-associated Jaks (Jak 1/3) are activated, inducing phosphorylation of a tyrosine residue within the cytoplasmic tail of IL-4Ra [3]. The phosphotyrosine (pY) 461 motif generated on the receptor then acts as a docking site to recruit STAT6, leading to the tyrosine phosphorylation of STAT6 by Jaks. Subsequently, phosphorylated STAT6 departs from the receptor, dimerizes, and translocates into the nucleus, where it turns on the expression of IL-4 target genes [3,4]. The IL-4-induced STAT6 activity is shown to be essential for the establishment of distal promoter activity for GATA3 transcription in developing Th2 cells [5]. IFNs are widely expressed cytokines with multiple biological act...

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“…IL-4, and IL-13 also, down-regulates indoleamine 2,3-dioxygenase (INDO) activity, which catalyzes tryptophan that is an essential amino acid for T. gondii growth within the host cells, activated by IFNs especially by IFN-γ [22,23]. Moreover, IFN-γ directly restricts the IL-4 action via inhibition of STAT6 signal transduction and gene expression [24] or by suppression of STAT6 phosphorylation by inhibiting its recruitment to the IL-4 receptor [25]. Intracellular infection of T. gondii leads to a blockade in NFκ B and STAT1 activation pathways.…”

Section: Discussionmentioning

confidence: 99%

IL-4 Independent Nuclear Translocalization of STAT6 in HeLa Cells by Entry of Toxoplasma gondii

2009

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INTRODUCTIONToxoplasma gondii is an obligate intracellular protozoan parasite and an important zoonotic pathogen that causes severe diseases in congenitally infected patients and in immunocompromised patients such as AIDS victims in addition to the parasite infecting healthy persons [1]. T. gondii infects macrophages primarily and is capable of invading and replicating within a wide variety of nucleated host cells.The signal transducer and activator of transcription (STAT) family of transcription factors mediate various extracellular cytokine signals into diverse biological responses via the modulation of gene transcription specific to the cytokines [2]. The participation of STAT proteins in immune regulation by cytokines from T. gondii infected host cells has been well established [3]. It has been well known that macrophages, dendritic cells, and polymorphonuclear cells secrete IL-12 in response to T. gondii infection [4,5]. IL-12, acting through STAT4, promotes the production of IFN-γ . Through intracellular signaling intermediates such as STAT1 and T-bet, IFN-γ can induce differentiation of Th1 lymphocytes and possibly CD8 + and NK cells [6]. IFN-γ signaling through STAT1 is also involved in promoting IL-12 production by antigen-presenting cells. More recent evidence indicates that STAT4 signaling promotes IFN-γ production from dendritic cells and macrophages. The major antimicrobial effects of IFN-γ during T. gondii infection, the generation of nitric oxide and induction of IFN-γ inducible GTP binding protein (IGTP) and LRG-47, are mediated through STAT1 [7,8]. Recently, it has been shown that cell invasion by T. gondii activates STAT3 of macrophages, which suppresses LPS-triggered TNF-αand IL-12 production [9]. We present, in this study, the evidence of nuclear translocation of STAT6 in the signaling during infection with T. gondii in host cells. This activation of host STAT6 after intracellular penetration of T. gondii resembles that of host cell stimulation by IL-4, which protects against the toxoplasmacidal action of IFN-γ . MATERIALS AND METHODS Parasite and host cellsThe RH strain of T. gondii was maintained by peritoneal passage in BALB/c mice. Prior to use, the tachyzoites were purified by centrifugation over 40% Percoll (Amersham Parmacia Biotech, Uppsala, Sweden) in PBS solution [10]. HeLa (ATCC CCL-2) cells were cultured in minimum essential medium (MEM) supplemented with 10% FBS and used as host cells. IL-4 Independent Nuclear Translocalization of STAT6 inHeLa Cells by Entry of Toxoplasma gondii Korean J Parasitol. Vol. 47, No. 2: 117-124, June 2009 DOI: 10.3347/kjp.2009 117 Abstract: Toxoplasma gondii provokes rapid and sustained nuclear translocation of the signal transducer and activator of transcription 6 (STAT6) in HeLa cells. We observed activation of STAT6 as early as 2 hr after infection with T. gondii by the nuclear translocation of fluorescence expressed from exogenously transfected pDsRed2-STAT6 plasmid and by the detection of phosphotyrosine-STAT6 in Western blot. STAT6 activation occ...

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IFN-γ Suppresses STAT6 Phosphorylation by Inhibiting Its Recruitment to the IL-4 Receptor

Cited by 27 publications

References 39 publications

Suppression of Th2 Cell Development by Notch Ligands Delta1 and Delta4

Suppression of Th2 Cell Development by Notch Ligands Delta1 and Delta4

Counter‐regulation mechanism of IL‐4 and IFN‐α signal transduction through cytosolic retention of the pY‐STAT6:pY‐STAT2:p48 complex

IL-4 Independent Nuclear Translocalization of STAT6 in HeLa Cells by Entry of Toxoplasma gondii

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