Viral infection and Toll‐like receptor agonists induce a differential expression of type I and λ interferons in human plasmacytoid and monocyte‐derived dendritic cells

Coccia, Eliana M.; Severa, Martina; Giacomini, Elena; Monneron, Danièle; Remoli, Maria Elena; Julkunen, Ilkka; Cella, Marina; Lande, Roberto; Uzé, Gilles

doi:10.1002/eji.200324610

Cited by 444 publications

(401 citation statements)

References 40 publications

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“…3A). Similar results were obtained for the luciferase-reporter construct driven by the promoter of IFN-λ1, type III IFN which is co-ordinately expressed with IFN-β in MDDCs in response to TLR4 stimulation [24] (Supporting Information Fig. 4).…”

Section: Inactivation Of Foxo3 In Response To Tlr4 Stimulation Is Reqsupporting

confidence: 80%

“…We examined the effect of FOXO3 expression on the transcriptional activity of IFN genes in response to TLR4 stimulation. IFN-β is the only type I IFN expressed in human MDDCs stimulated with LPS [24]. Co-expression of FOXO3 together with the luciferase-reporter construct driven by the IFN-β promoter in 293-TLR4 cells blocked its LPS-induced transcriptional activity (Fig.…”

Section: Inactivation Of Foxo3 In Response To Tlr4 Stimulation Is Reqmentioning

confidence: 91%

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FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

et al. 2012

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Cell survival transcription factor FOXO3 has been recently implicated in moderating proinflammatory cytokine production by dendritic cells (DCs), but the molecular mechanisms are unclear. It was suggested that FOXO3 could antagonize NF-κB activity, while IKK-β was demonstrated to inactivate FOXO3, suggesting a cross-talk between the two pathways. Therefore, FOXO3 activity must be tightly regulated to allow for an appropriate inflammatory response. Here, we show that in human monocyte-derived DCs (MDDCs), FOXO3 is able to antagonize signaling intermediates downstream of the Toll-like receptor (TLR) 4, such as NF-κB and interferon regulatory factors (IRFs), resulting in inhibition of interferon (IFN)-β expression.We also demonstrate that the activity of FOXO3 itself is regulated by IKK-ε, a kinase involved in IFN-β production, which phosphorylates and inactivates FOXO3 in response to TLR4 agonists. Thus, we identify FOXO3 as a new IKK-ε-controlled check-point of IRF activation and regulation of IFN-β expression, providing new insight into the role of FOXO3 in immune response control.Keywords: Activation-induced cell death r Cell volume regulation r T-cell response r Taurine transporter Supporting Information available online IntroductionThe FOXO transcription factors (FOXO1, FOXO3, FOXO4, and FOXO6) are involved in a wide range of cellular processes including cell-cycle arrest, apoptosis, oxidative stress detoxification, and cellular homeostasis [1][2][3]. Given their importance in such critical cellular functions, their activity is tightly regulated by posttranslational modifications, mainly via the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway [4]. In response to growth factors or cytokines, FOXO proteins are phosphorylated by AKT Correspondence: Dr. Lionel Luron e-mail: luron@ciml.univ-mrs.fr at three conserved serine/threonine residues (Thr 32 , Ser 253 , and Ser 315 of FOXO3) resulting in the protein inactivation via nuclear exclusion and subsequent degradation [5,6].More recently, FOXO factors have been shown to play a role in immunity and inflammation [7][8][9][10][11]. In addition to their critical role in homeostasis of immune-relevant cells including B and T cells [7][8][9], FOXOs are associated with inflammatory diseases [12,13]. Moreover, FOXO3 was identified as a key factor in regulation of the innate immune response [10]. In FOXO3-deficient mice, production of major proinflammatory cytokines IL-6 and TNF-α by dendritic cells (DCs) is increased in response to viral infection, resulting in a greater expansion of T-cell population [10]. Expression of proinflammatory cytokines as well as type I interferons (IFNs) in response to viral and microbial stimuli is regulated by a number of key transcription factors, including NF-κB and [20,21]. Interestingly, its overexpression in a breast cancer model system could functionally replace PI3K constitutive activation and prevent cell-cycle arrest and apoptosis [20], processes often mediated by FOXO3 target genes, such as Cyclin D, p27/KIP1, FasL, bim...

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Section: Inactivation Of Foxo3 In Response To Tlr4 Stimulation Is Reqsupporting

confidence: 80%

Section: Inactivation Of Foxo3 In Response To Tlr4 Stimulation Is Reqmentioning

confidence: 91%

FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

et al. 2012

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“…[64][65][66][67] Unlike other types of DCs, pDCs constitutively express high levels of IRF7. 68,69 Furthermore, treatment of pDCs with TLR9 ligands causes nuclear translocation of IRF7, and pDCs derived from IRF7-deficient mice are incapable of producing type I IFN in response to TLR7/8 and TLR9 ligands. 64,65 Thus, IRF7 is an essential transcription factor that regulates type I IFN induction in pDCs.…”

Section: Activation Of Irfs By Tlr7/8 and Tlr9mentioning

confidence: 99%

TLR signaling

2006

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The Toll-like receptor (TLR) family plays an instructive role in innate immune responses against microbial pathogens, as well as the subsequent induction of adaptive immune responses. TLRs recognize specific molecular patterns found in a broad range of microbial pathogens such as bacteria and viruses, triggering inflammatory and antiviral responses and dendritic cell maturation, which result in the eradication of invading pathogens. Individual TLRs interact with different combinations of adapter proteins and activate various transcription factors such as nuclear factor (NF)-jB, activating protein-1 and interferon regulatory factors, driving a specific immune response. This review outlines the recent advances in our understanding of TLR-signaling pathways and their roles in immune responses. Further, we also discuss a new concept of TLR-independent mechanisms for recognition of microbial pathogens.

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“…The importance of Tyk-2 in autoimmunity is further supported by the observation that Tyk-2-deficient mice are resistant to experimental arthritis (57). IRF-5, in contrast, is important for induction of IFN␣ production by viral infections and TLR-7/8 agonists and is constitutively expressed in NIPCs/PDCs (58,59). In addition, IRF-5 increases the expression of several other genes involved in cell signaling, apoptosis, cell cycle regulation, and immune activation (60).…”

Section: Introductionmentioning

confidence: 94%