IFNγ mediates DUOX2 expression via a STAT-independent signaling pathway

Hill, Thomas M.; Xu, Changhong; Harper, Richart W

doi:10.1016/j.bbrc.2010.04.004

Cited by 13 publications

(7 citation statements)

References 30 publications

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“…To date, the regulation of DUOX2/DUOXA2 expression has been mainly investigated in thyrocytes, as well as in airways and gut epithelial cells following bacterial infection [6,[27][28][29]. Our observation that DUOX2/ DUOXA2 were induced following SeV infection in three different AEC models, A549, ALI-Calu-3 and NHBEs, adds to the picture of the previously reported RV-induced DUOX2/DUOXA2 expression in primary AECs [6,[30][31][32].…”

Section: Rsv Interferes With the Expression Of Duox2supporting

confidence: 69%

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

et al. 2013

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Airway epithelial cells are key initial innate immune responders in the fight against respiratory viruses, primarily via the secretion of antiviral and proinflammatory cytokines that act in an autocrine/paracrine fashion to trigger the establishment of an antiviral state. It is currently thought that the early antiviral state in airway epithelial cells primarily relies on IFNβ secretion and the subsequent activation of the interferon-stimulated gene factor 3 (ISGF3) transcription factor complex, composed of STAT1, STAT2 and IRF9, which regulates the expression of a panoply of interferon-stimulated genes encoding proteins with antiviral activities. However, the specific pathways engaged by the synergistic action of different cytokines during viral infections, and the resulting physiological outcomes are still ill-defined. Here, we unveil a novel delayed antiviral response in the airways, which is initiated by the synergistic autocrine/paracrine action of IFNβ and TNFα, and signals through a non-canonical STAT2-and IRF9-dependent, but STAT1-independent cascade. This pathway ultimately leads to the late induction of the DUOX2 NADPH oxidase expression. Importantly, our study uncovers that the development of the antiviral state relies on DUOX2-dependent H 2 O 2 production. Key antiviral pathways are often targeted by evasion strategies evolved by various pathogenic viruses. In this regard, the importance of the novel DUOX2-dependent antiviral pathway is further underlined by the observation that the human respiratory syncytial virus is able to subvert DUOX2 induction.

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Section: Rsv Interferes With the Expression Of Duox2supporting

confidence: 69%

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

et al. 2013

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“…The transcriptional regulation of Duox1 and Duox2 by inflammatory cytokines in the lung epithelium suggests distinct roles for Duox1 and Duox2 proteins in host defense [205] . The Th-2 cytokines IL-4 and IL-13 increased Duox1 expression by up to 5-fold, while Duox2 was induced up to 25-fold, either with IFN-γ treatment (a Th-1 cytokine) or with the viral mimic polyinosine-polycytidylic acid (poly (I:C)), indicating a role for Duox2 in viral clearance, which was confirmed in several subsequent studies [136,205,221,222] .…”

Section: Hypothyroidism – Spotlight On Duox2/duoxa2supporting

confidence: 55%

Genetic disorders coupled to ROS deficiency

et al. 2015

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Maintaining the redox balance between generation and elimination of reactive oxygen species (ROS) is critical for health. Disturbances such as continuously elevated ROS levels will result in oxidative stress and development of disease, but likewise, insufficient ROS production will be detrimental to health. Reduced or even complete loss of ROS generation originates mainly from inactivating variants in genes encoding for NADPH oxidase complexes. In particular, deficiency in phagocyte Nox2 oxidase function due to genetic variants (CYBB, CYBA, NCF1, NCF2, NCF4) has been recognized as a direct cause of chronic granulomatous disease (CGD), an inherited immune disorder. More recently, additional diseases have been linked to functionally altered variants in genes encoding for other NADPH oxidases, such as for DUOX2/DUOXA2 in congenital hypothyroidism, or for the Nox2 complex, NOX1 and DUOX2 as risk factors for inflammatory bowel disease. A comprehensive overview of novel developments in terms of Nox/Duox-deficiency disorders is presented, combined with insights gained from structure–function studies that will aid in predicting functional defects of clinical variants.

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“…Recent studies suggest the existence of alternative signaling events that either substitute for or act in parallel with JAK-STAT signaling 80 , 81 . It is of note that such JAK-STAT-independent mechanisms have been previously implicated in IFNγ-induced impairment of the paracellular barrier in intestinal epithelial cells 82 .…”

Section: Discussionmentioning

confidence: 99%

Novel mechanism of cytokine-induced disruption of epithelial barriers

et al. 2013

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The ductal epithelium plays a key role in physiological secretion of pancreatic enzymes into the digestive system. Loss of barrier properties of the pancreatic duct may contribute to the development of pancreatitis and metastatic dissemination of pancreatic tumors. Proinflammatory cytokines are essential mediators of pancreatic inflammation and tumor progression; however, their effects on the integrity and barrier properties of the ductal epithelium have not been previously addressed. In the present study, we investigate mechanisms of cytokine-induced disassembly of tight junctions (TJs) and adherens junctions (AJs) in a model pancreatic epithelium. Exposure of HPAF-II human pancreatic epithelial cell monolayers to interferon (IFN)γ disrupted integrity and function of apical junctions as manifested by increased epithelial permeability and cytosolic translocation of AJ and TJ proteins. Tumor necrosis factor (TNF)α potentiated the effects of IFNγ on pancreatic epithelial junctions. The cytokine-induced increase in epithelial permeability and AJ/TJ disassembly was attenuated by pharmacological inhibition of Janus kinase (JAK) and protein kinase D (PKD). Loss of apical junctions in IFNγ/TNFα-treated HPAF-II cells was accompanied by JAK and PKD dependent decrease in expression of AJ (E-cadherin, p120 catenin) and TJ (occludin, ZO-1) proteins. Depletion of E-cadherin or p120 catenin recapitulated the effects of cytokines on HPAF-II cell permeability and junctions. Our data suggests that proinflammatory cytokines disrupt pancreatic epithelial barrier via expressional downregulation of key structural components of AJs and TJs. This mechanism is likely to be important for pancreatic inflammatory injury and tumorigenesis.

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IFNγ mediates DUOX2 expression via a STAT-independent signaling pathway

Cited by 13 publications

References 30 publications

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

Genetic disorders coupled to ROS deficiency

Novel mechanism of cytokine-induced disruption of epithelial barriers

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