IκB Kinase ε Targets Interferon Regulatory Factor 1 in Activated T Lymphocytes

Sgarbanti, Marco; Marsili, Giulia; Remoli, Anna Lisa; Stellacci, Emilia; Mai, Antonello; Rotili, Dante; Perrotti, Edvige; Acchioni, Chiara; Orsatti, Roberto; Iraci, Nunzio; Ferrari, Mathieu; Borsetti, Alessândra; Hiscott, John; Battistini, Angela

doi:10.1128/mcb.01161-13

Cited by 31 publications

(33 citation statements)

References 46 publications

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“…Although phosphorylation of DrIRF1 is observed, its physiological relevance remains to be determined. Interestingly, a recent study showed that phosphorylation of human IRF1 in primary CD4 + T cells blocks induction of IFN-b following treatment with poly(I:C) (57).…”

Section: Discussionmentioning

confidence: 99%

Zebrafish IRF1, IRF3, and IRF7 Differentially Regulate IFNΦ1 and IFNΦ3 Expression through Assembly of Homo- or Heteroprotein Complexes

Feng

Zhang

et al. 2016

The Journal of Immunology

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In mammals, IFN regulatory factor (IRF)1, IRF3, and IRF7 are three critical transcription factors that are pivotal for cooperative regulation of the type I IFN response. In this study, we explored the relative contribution of zebrafish (Danio rerio) IRF1 (DrIRF1), IRF3 (DrIRF3), and IRF7 (DrIRF7) (DrIRF1/3/7) to zebrafish IFNΦ1 (DrIFNΦ1) and IFNΦ3 (DrIFNΦ3) (DrIFNΦ1/3) activation. Following spring viremia of carp virus infection, DrIFNΦ1/3 and DrIRF1/3/7 transcripts are significantly induced in zebrafish tissues, which correlates with the replication of spring viremia of carp virus. DrIRF1/3/7 selectively bind to the IRF-binding element/IFN-stimulated regulatory element sites of DrIFNΦ1/3 promoters, with the exception that DrIRF3 has no preference for two IRF-binding element/IFN-stimulated regulatory element motifs within the DrIFNΦ3 promoter. Consistently, DrIRF3 alone activates DrIFNΦ1, but not DrIFNΦ3; DrIRF7 predominantly stimulates DrIFNΦ3; and DrIRF1 has similar potential to DrIFNΦ1 and DrIFNΦ3. Strikingly, DrIRF3 facilitates the binding of DrIRF1 and DrIRF7 to both zebrafish IFN promoters, and so does DrIRF7 for the binding of DrIRF1, particularly to the DrIFNΦ3 promoter. These binding properties correlate with differential responses of DrIFNΦ1 and DrIFNΦ3 to the combinatory stimulation of DrIRF1/3/7, depending on their relative amounts. Similar to the dual roles of human IRF3 in regulating IRF7-activated IFNα genes, DrIRF3 exerts dual effects on DrIRF1-mediated DrIFNΦ3 gene expression: an inhibitory effect at lower concentrations and a synergistic effect at higher concentrations. These data provide evidence that fish and mammals have evolved a similar IRF-dependent regulatory mechanism fine-tuning IFN gene activation.

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Section: Discussionmentioning

confidence: 99%

Zebrafish IRF1, IRF3, and IRF7 Differentially Regulate IFNΦ1 and IFNΦ3 Expression through Assembly of Homo- or Heteroprotein Complexes

Feng

Zhang

et al. 2016

The Journal of Immunology

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“…Notably, mammalian IRF1 activation through phosphorylation is poorly understood, despite evidence for the involvement of phosphorylation (55,56). Interestingly, a recent study showed that phosphorylation of human IRF1 at aa 215/219/221 by IKK-ε in primary CD4 + T cells blocks its transcriptional activity and subsequent induction of IFN-b following treatment with poly(I:C) (57). In addition, MyD88 binding likely results in the activation of human IRF1, because a rapid migration to the nucleus is observed when human IRF1 forms a complex with MyD88 (6).…”

mentioning

confidence: 99%

Zebrafish IRF1 Regulates IFN Antiviral Response through Binding to IFNϕ1 and IFNϕ3 Promoters Downstream of MyD88 Signaling

Feng

Zhang

et al. 2015

The Journal of Immunology

102

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In mammals, type I IFNs (mainly IFN-α/β) are primarily regulated by transcription factors of the IFN regulatory factor (IRF) family. Fish IFNs do not show a one-to-one orthologous relationship with mammalian type I IFN homologues. Using a bacterial one-hybrid reporter screening system and an overexpression approach to explore the molecular mechanism underlying fish IFN induction, we identified zebrafish Danio rerio IRF (DrIRF)1 as a positive regulator of the fish IFN antiviral response. Among 12 zebrafish IRF family genes, DrIRF1 is most abundant in zebrafish immune tissues, including head kidney and spleen; upon virus infection, it is one of most significantly induced genes. Overexpression of DrIRF1 induces the expression of IFN and IFN-stimulated genes, hence protecting epithelioma papulosum cyprini cells against spring viremia of carp virus infection. As a transcription factor with constitutively nuclear retention, DrIRF1 directly binds to the IFN-stimulated regulatory element/IRF-binding element sites of zebrafish IFN promoters, which are dependent on four conserved amino acids of the N-terminal DNA-binding domain helix α3 motif. Mutation of either residue reveals a differential requirement for DrIRF1-mediated activation of zebrafish IFNϕ1 and IFNϕ3 promoters. Notably, C-terminal phosphorylation of DrIRF1 is observed and is not required for in vitro binding of DrIRF1 to fish IFN promoters. Unlike DrIRF3 and DrIRF7, which are responsible for differential expression of zebrafish IFNϕ1 and IFNϕ3 through the retinoic acid–inducible gene I–like receptor pathway, DrIRF1 works in concert with MyD88 to activate zebrafish IFNϕ3 but not IFNϕ1. These results provide insights into the evolving function of IRF1 as a positive IFN regulator.

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“…Several of these were gene products known to have inhibitory effects on nuclear factor "kappa-light-chain-enhancer" of activated B cells (NF-kB), a central molecule during T-cell activation, including RhoH and IkB kinase (IKK)-e. RhoH interferes with other Rho GTPases to block NF-kB and p38 activation, 44 IKK-e interferes with RelA, and diminishes IFN-b production. 45 Another gene identified in this analysis, Trim28, plays a key role in immune tolerance. 46 Thus, anti-CD132 mAb modulates a variety of pathways and factors in the cell which are linked to reduced T-cell activation.…”

Section: Discussionmentioning

confidence: 93%

Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD

Hechinger¹,

Smith²,

Flynn

et al. 2015

Blood

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Key Points• Monoclonal antibody blockade of the common g chain attenuates acute and chronic GVHD.• Common g-chain cytokines increase granzyme B levels in CD8 T cells, which are reduced upon CD132 blockade in vivo.The common g chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-g, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3 2/2 T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common g-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation. (Blood. 2015;125(3):570-580)

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IκB Kinase ε Targets Interferon Regulatory Factor 1 in Activated T Lymphocytes

Cited by 31 publications

References 46 publications

Zebrafish IRF1, IRF3, and IRF7 Differentially Regulate IFNΦ1 and IFNΦ3 Expression through Assembly of Homo- or Heteroprotein Complexes

Zebrafish IRF1, IRF3, and IRF7 Differentially Regulate IFNΦ1 and IFNΦ3 Expression through Assembly of Homo- or Heteroprotein Complexes

Zebrafish IRF1 Regulates IFN Antiviral Response through Binding to IFNϕ1 and IFNϕ3 Promoters Downstream of MyD88 Signaling

Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD

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