Cell proliferation and survival induced by Toll-like receptors is antagonized by type I IFNs

Hasan, Uzma; Caux, Christophe; Perrot, Ivan; Doffin, Anne-Claire; Ménétrier‐Caux, Christine; Trinchieri, Giorgio; Tommasino, Massimo; Vlach, Jaromir

doi:10.1073/pnas.0700664104

Cited by 72 publications

(77 citation statements)

References 51 publications

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“…The present data support a switching function of type I IFN in the functional outcome of TLR triggering in tumor cells, as it has been recently shown in DC (37). Indeed, TLR3 triggering induces NF-B activation in tumor cells regardless of their fate, but only cells producing IFN-␣ through the p38 MAPK pathway are induced into apoptosis.…”

Section: Discussionsupporting

confidence: 65%

TLR3 Ligand Induces NF-κB Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-α Production

Chiron

Pellat‐Deceunynck

Amiot

et al. 2009

The Journal of Immunology

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Multiple myeloma (MM) cells express TLR. It has been shown that TLR ligands induce the proliferation, survival, and immune surveillance escape of MM cells through MyD88-TLR pathways. Deciphering TLR function in MM cells will help in understanding the mechanisms of tumor cell growth. In this study, we examined the response of MM cells to the MyD88-independent/TIR-domain-containing adapter-inducing IFN-β-dependent TLR3. Deregulation of NF-κB pathway is a feature of MM cells, and we wondered whether TLR3 activation could mobilize the NF-κB pathway. We show that five of seven human myeloma cell line (HMCL) cells expressed TLR3. In the presence of the synthetic TLR3 ligand (poly(I:C)), activation of NF-κB pathway was observed in three of five selected TLR3+ HMCL, NCI-H929, RPMI 8226, and KMM1. In agreement with NF-κB activation, only these three HMCL responded to poly(I:C), although by either an increase (KMM1) or a decrease (NCI-H929, RPMI 8226) of proliferation. We show that KMM1 increase of proliferation was prevented by NF-κB inhibitor. In contrast, inhibition of proliferation in both NCI-H929 and RPMI 8226 was due to IFN-α-induced apoptosis. We next demonstrated that p38 MAPK pathway controlled both IFN-α secretion and IFN-α-mediated cell death. Moreover, cell death also involved activation of ERK1/2 pathway. In conclusion, our results show that TLR3 ligand induces NF-κB pathway activation in MM and support a switching function of type I IFN in the functional outcome of TLR3 triggering in tumor cells.

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Section: Discussionsupporting

confidence: 65%

TLR3 Ligand Induces NF-κB Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-α Production

Chiron

Pellat‐Deceunynck

Amiot

et al. 2009

The Journal of Immunology

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“…In fact, TBK1 has been reported to promote tumor growth and proliferation of HUVECs (27). Hasan et al (28) reported that TRIF/TBK1 regulates phosphorylation of the cell cycle inhibitor p27 kip1 and proteasome degradation. Because phosphorylation of p27 can be induced by Akt (29), our results suggest that TRIF/TBK1-induced phosphorylation and degradation of p27 is at least partly mediated by Akt after it is activated by TBK1.…”

Section: Discussionmentioning

confidence: 99%

Akt Contributes to Activation of the TRIF-Dependent Signaling Pathways of TLRs by Interacting with TANK-Binding Kinase 1

Joung

Park²,

Rani³

et al. 2011

The Journal of Immunology

115

116

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Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF) is an adaptor molecule that is recruited to TLR3 and -4 upon agonist stimulation and triggers activation of IFN regulatory factor 3 (IRF3) and expression of type 1 IFNs, which are critical for cellular antiviral responses. We show that Akt is a downstream molecule of TRIF/TANK-binding kinase 1 (TBK1) and plays an important role in the activation of IRF3 by TLR3 and -4 agonists. Blockade of Akt by a dominant-negative mutant or by short interfering RNA decreased IRF3 activation and IFN-β expression induced by polyinosinic:polycytidylic acid [poly(I:C)], LPS, TRIF, and TBK1. Association of endogenous TBK1 and Akt was observed in macrophages when stimulated with poly(I:C) and LPS. In vitro kinase assays combined with reversed-phase liquid chromatography mass spectrometry analysis showed that TBK1 enhanced phosphorylation of Akt on Ser473, whereas knockdown of TBK1 expression by short interfering RNA in macrophages decreased poly(I:C)- and LPS-induced Akt phosphorylation. Embryonic fibroblasts derived from TBK1 knockout mice also showed impaired Akt phosphorylation in response to poly(I:C) and LPS. To our knowledge, our results demonstrate a new regulatory mechanism for Akt activation mediated by TBK1 and a novel role of Akt in TLR-mediated immune responses.

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“…It has been reported that IKKα can reduce overall p27 levels independent of IFN signaling and the TLR-NFκB signaling pathway may represent an additional TLR-mediated pathway involved in regulating cell cycle entry and exit. 37 Therefore, because IKKα is a known regulator of 14-3-3σ, it is possible that IRF6, 14-3-3σ, and IKKα function through similar pathways, perhaps in coordination with TLR3 signaling, to regulate specific cell cycle events that are necessary for exit from the cell cycle and entry into the G(0) differentiation phase.…”

Section: Irf6 As a Transcription Factormentioning

confidence: 99%

“…34,35 Work by Hasan and colleagues has suggested that signaling through TLR3 and TLR4 following stimulation with their respective ligands polyI:C (a synthetic double stranded RNA) and lipopolysaccharide (LPS) can induce entry into the cell cycle, but only in the absence of type I IFN signaling, which is also regulated through TLR signaling pathways. 36,37 Because IRFs are known regulators of type I IFN, it is possible that IRF6 functions through canonical TLR-IRF signaling pathways to induce type I IFN as a means of promoting quiescence and differentiation.…”

Section: Irf6 As a Transcription Factormentioning

confidence: 99%

IRF6 in development and disease: A mediator of quiescence and differentiation

Bailey

Hendrix²

2008

Cell Cycle

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Post utero development of the mammary gland is a complex developmental process characterized by states of rapid cell proliferation (branching morphogenesis) followed by functional differentiation (lactation) and the consequent apoptosis (involution) of the secretory mammary epithelial cell. This process is cyclical, such that involution returns the mammary gland to a near-virgin-like state capable of responding to morphogenic cues with each consecutive pregnancy. Importantly, many of the regulatory processes which oversee mammary gland development are corrupted or otherwise compromised during the development of breast cancer. For example, Interferon Regulatory Factor 6 (IRF6) is a novel protein with growth inhibitory properties that was initially identified in mammary epithelial cells through its interaction with maspin, a known tumor suppressor in normal breast tissue. Recent findings from our laboratory suggest that IRF6 functions synergistically with maspin to regulate mammary epithelial cell differentiation by acting on the cell cycle. This perspective focuses on the possible involvement of IRF6 in promoting differentiation by regulating exit from the cell cycle and entry into the G(0) phase of cellular quiescence, and how these new findings shed light on normal mammary gland development and the initiation and progression of breast cancer.

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Cell proliferation and survival induced by Toll-like receptors is antagonized by type I IFNs

Cited by 72 publications

References 51 publications

TLR3 Ligand Induces NF-κB Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-α Production

TLR3 Ligand Induces NF-κB Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-α Production

Akt Contributes to Activation of the TRIF-Dependent Signaling Pathways of TLRs by Interacting with TANK-Binding Kinase 1

IRF6 in development and disease: A mediator of quiescence and differentiation

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