scholarly journals Type I Interferons Control Proliferation and Function of the Intestinal Epithelium

2016 ◽  
Vol 36 (7) ◽  
pp. 1124-1135 ◽  
Author(s):  
Yuliya V. Katlinskaya ◽  
Kanstantsin V. Katlinski ◽  
Audrey Lasri ◽  
Ning Li ◽  
Daniel P. Beiting ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Type I Interferons ◽  
Type I ◽  
Cell Renewal ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Antiproliferative Effects ◽  
Genetic Ablation ◽  
And Function ◽  
Intestinal Hyperplasia

Wnt pathway-driven proliferation and renewal of the intestinal epithelium must be tightly controlled to prevent development of cancer and barrier dysfunction. Although type I interferons (IFN) produced in the gut under the influence of microbiota are known for their antiproliferative effects, the role of these cytokines in regulating intestinal epithelial cell renewal is largely unknown. Here we report a novel role for IFN in the context of intestinal knockout of casein kinase 1α (CK1α), which controls the ubiquitination and degradation of both β-catenin and the IFNAR1 chain of the IFN receptor. Ablation of CK1α leads to the activation of both β-catenin and IFN pathways and prevents the unlimited proliferation of intestinal epithelial cells despite constitutive β-catenin activity. IFN signaling contributes to the activation of the p53 pathway and the appearance of apoptotic and senescence markers in the CK1α-deficient gut. Concurrent genetic ablation of CK1α and IFNAR1 leads to intestinal hyperplasia, robust attenuation of apoptosis, and rapid and lethal loss of barrier function. These data indicate that IFN play an important role in controlling the proliferation and function of the intestinal epithelium in the context of β-catenin activation.

Type I Interferons promote maintenance and function of follicular T helper cells in vitro

2019 ◽  
Author(s):  
S Ehrlich ◽  
K Wild ◽  
M Smits ◽  
K Zoldan ◽  
M Hofmann ◽  
...  
Keyword(s):  
T Helper Cells ◽  
Type I Interferons ◽  
Type I ◽  
T Helper ◽  
Helper Cells ◽  
Follicular T Helper Cells ◽  
And Function

The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor α signaling

Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 454-464 ◽  
Author(s):  
Cyril Seillet ◽  
Sophie Laffont ◽  
Florence Trémollières ◽  
Nelly Rouquié ◽  
Claude Ribot ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Type I ◽  
Genetic Ablation ◽  
17Β Estradiol ◽  
Female Host

Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFN-α/β) in response to viral or endogenous nucleic acids through activation of their endosomal Toll-like receptors (TLR-7 and TLR-9). Enhanced TLR-7–mediated IFN-α production by pDCs in women, compared with men, has been reported, but whether sex hormones, such as estrogens, are involved in this sex-based difference is unknown. Here we show, in humanized mice, that the TLR-7–mediated response of human pDCs is increased in female host mice relative to male. In a clinical trial, we establish that treatment of postmenopausal women with 17β-estradiol markedly enhances TLR-7– and TLR-9–dependent production of IFN-α by pDCs stimulated by synthetic ligands or by nucleic acid-containing immune complexes. In mice, we found exogenous and endogenous estrogens to promote the TLR-mediated cytokine secretion by pDCs through hematopoietic expression of estrogen receptor (ER) α. Genetic ablation of ERα gene in the DC lineage abrogated the enhancing effect of 17β-estradiol on their TLR-mediated production of IFN-α, showing that estrogens directly target pDCs in vivo. Our results uncover a previously unappreciated role for estrogens in regulating the innate functions of pDCs, which may account for sex-based differences in autoimmune and infectious diseases.

scholarly journals Rotavirus Degrades Multiple Interferon (IFN) Type Receptors To Inhibit IFN Signaling and Protects against Mortality from Endotoxin in Suckling Mice

2017 ◽  
Vol 92 (1) ◽  
Author(s):  
Adrish Sen ◽  
Ayushi Sharma ◽  
Harry B. Greenberg
Keyword(s):  
Intestinal Epithelial Cells ◽  
Degradation Pathway ◽  
Type I ◽  
Intestinal Epithelial ◽  
Genetic Ablation ◽  
Suckling Mice ◽  
Infected Cells ◽  
New Research

ABSTRACTSTAT1 phosphorylation in response to exogenous interferon (IFN) administration can be inhibited by rotaviral replication bothin vitroandin vivo. In addition many rotavirus strains are resistant to the actions of different IFN types. The regulation by rotaviruses (RVs) of antiviral pathways mediated by multiple IFN types is not well understood. In this study, we find that during infectionin vitroandin vivo, RVs significantly deplete IFN type I, II, and III receptors (IFNRs). Regulation of IFNRs occurred exclusively within RV-infected cells and could be abrogated by inhibiting the lysosomal-endosomal degradation pathway.In vitro, IFNR degradation was conserved across multiple RV strains that differ in their modes of regulating IFN induction. In suckling mice, exogenously administered type I, II, or III IFN induced phosphorylation of STAT1-Y701 within intestinal epithelial cells (IECs) of suckling mice. Murine EW strain RV infection transiently activated intestinal STAT1 at 1 day postinfection (dpi) but not subsequently at 2 to 3 dpi. In response to injection of purified IFN-α/β or -λ, IECs in EW-infected mice exhibited impaired STAT1-Y701 phosphorylation, correlating with depletion of different intestinal IFNRs and impaired IFN-mediated transcription. The ability of EW murine RV to inhibit multiple IFN types led us to test protection of suckling mice from endotoxin-mediated shock, an outcome that is dependent on the host IFN response. Compared to mortality in controls, mice infected with EW murine RV were substantially protected against mortality following parenteral endotoxin administration. These studies identify a novel mechanism of IFN subversion by RV and reveal an unexpected protective effect of RV infection on endotoxin-mediated shock in suckling mice.IMPORTANCEAntiviral functions of types I, II, and III IFNs are mediated by receptor-dependent activation of STAT1. Here, we find that RV degrades the types I, II, and III IFN receptors (IFNRs)in vitro. In a suckling mouse model, RV effectively blocked STAT1 activation and transcription following injection of different purified IFNs. This correlated with significantly decreased protein expression of intestinal types I and II IFNRs. Recent studies demonstrate that in mice lipopolysaccharide (LPS)-induced lethality is prevented by genetic ablation of IFN signaling genes such as IFNAR1 and STAT1. When suckling mice were infected with RV, they were substantially protected from lethal exposure to endotoxin. These findings provide novel insights into the mechanisms underlying rotavirus regulation of different interferons and are likely to stimulate new research into both rotavirus pathogenesis and endotoxemia.

scholarly journals Sex differences and similarities in the neuroimmune response to central administration of poly I:C

2020 ◽  
Author(s):  
Caitlin K. Posillico ◽  
Rosa E. Garcia-Hernandez ◽  
Natalie C. Tronson
Keyword(s):  
Sex Differences ◽  
Neurological Diseases ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Central Administration ◽  
Protein Levels ◽  
Males And Females ◽  
And Function ◽  
Neuroimmune Activation

ABSTRACTThe neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Aberrant neuroimmune activation is associated with dysregulation of memory and emotion, though the precise mechanisms at play are complex and highly context dependent. Sex differences neuroimmune activation and function further complicate our understanding of its roles in cognitive and affective regulation. Here, we characterized the physiological sickness and inflammatory response of the hippocampus following intracerebroventricular (ICV) administration of a synthetic viral mimic, polyinosinic:polycytidylic acid (poly I:C), in both male and female C57Bl/6 mice. We observed that poly I:C induced weight loss, fever, and elevations of cytokine and chemokines in the hippocampus of both sexes. Specifically, we found transient increases in gene expression and protein levels of IL-1a, IL-1β, IL-4, IL-6, TNFa, CCL2, and CXCL10, where males showed a greater magnitude of response compared with females. Only males showed increased IFNa and IFNγ in response to poly I:C, whereas both males and females exhibited elevations of IFNβ, demonstrating a specific sex difference in the anti-viral response in the hippocampus. This suggests that type I interferons are one potential node mediating sex-specific cytokine responses and neuroimmune effects on synaptic plasticity and cognition. These findings highlight the importance of using both males and females and analyzing a broad set of inflammatory markers in order to identify the precise, sex-specific roles for neuroimmune dysregulation in neurological diseases and disorders including Alzheimer’s Disease and depression.

scholarly journals N-Acetyl Serotonin Alleviates Oxidative Damage by Activating Nuclear Factor Erythroid 2-Related Factor 2 Signaling in Porcine Enterocytes

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 303
Author(s):  
Haiwei Liang ◽  
Ning Liu ◽  
Renjie Wang ◽  
Yunchang Zhang ◽  
Jingqing Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gastrointestinal Diseases ◽  
Mucosal Barrier ◽  
Related Factor ◽  
Protective Effects ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Downstream Target ◽  
Underlying Mechanisms ◽  
And Function

Apoptosis of intestinal epithelial cells following oxidative stress is a major cause of mucosal barrier dysfunction and is associated with the pathogenesis of various gastrointestinal diseases. Although L-tryptophan (Trp) is known to improve intestinal integrity and function, a beneficial effect of N-acetyl serotonin (NAS), a metabolite of Trp, on the apoptosis of enterocytes and the underlying mechanisms remain largely unknown. In the present study, we showed that porcine enterocytes treated with 4-hydroxy-2-nonenal (4-HNE), a metabolite of lipid peroxidation, led to upregulation of apoptotic proteins, including Bax and cleaved caspase-3, and reduction of tight junction proteins. These effects of 4-HNE were significantly abrogated by NAS. In addition, NAS reduced ROS accumulation while increasing the intracellular concentration of glutathione (GSH), and the abundance of the Nrf2 protein in the nucleus and its downstream target proteins. Importantly, these protective effects of NAS were abrogated by Atra, an inhibitor of Nrf2, indicating a dependence on Nrf2 signaling. Taken together, we demonstrated that NAS attenuated oxidative stress-induced cellular injury in porcine enterocytes by regulating Nrf2 signaling. These findings provide new insights into a functional role of NAS in maintaining intestinal homeostasis.

Interferon-α and -β inhibit the in vitro differentiation of immunocompetent human dendritic cells from CD14+ precursors

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 210-217 ◽  
Author(s):  
Bradford L. McRae ◽  
Taro Nagai ◽  
Roshanak Tolouei Semnani ◽  
Jean Maguire van Seventer ◽  
Gijs A. van Seventer
Keyword(s):  
T Cell ◽  
Type I Interferons ◽  
Interferon Α ◽  
Type I ◽  
Cell Secretion ◽  
Gm Csf ◽  
Th Cell ◽  
Acquired Immune Responses ◽  
And Function

Dendritic cell (DC) precursors and immature DC reside in epithelium where they encounter pathogens and cytokines, which stimulate their differentiation. We hypothesized that type-I interferons (IFN- and -β), cytokines that are produced early in the innate immune response against viruses and some bacteria, may influence DC differentiation and function. To examine this possibility, we used an in vitro model of DC differentiation in which initial culture of human CD14+monocytes with granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 generates immature DC, and subsequent culture with tumor necrosis factor (TNF)- drives the final development into mature DC. We found in this model that IFN-/β, added from the initiation of the culture on, significantly reduced the survival and altered the morphology and differentiation of DC. TNF-–dependent maturation of IFN-β–treated immature DC led to cells with reduced expression of CD1a, CD40, CD54, and CD80 when compared with mature DC controls. IFN-/β–treated DC further had a reduced capacity to induce naive Th-cell proliferation through allostimulation or anti-CD3 monoclonal antibody stimulation. In addition, IFN-/β–treated DC secreted less IL-12 upon stimulation with Staphylococcus aureus Cowan strain or with CD4+ T cells, and this decrease correlated directly with their inability to support CD4+ T-cell secretion of IFN-γ, even though T-cell lymphotoxin production was unaffected. These findings indicate that type-I IFNs can influence the generation of acquired immune responses by modifying T-helper cell differentiation through the regulation of DC differentiation and function.

scholarly journals The transcription factor Spi-B regulates human plasmacytoid dendritic cell survival through direct induction of the antiapoptotic gene BCL2-A1

Blood ◽  
2012 ◽  
Vol 119 (22) ◽  
pp. 5191-5200 ◽  
Author(s):  
Julien J. Karrich ◽  
Melania Balzarolo ◽  
Heike Schmidlin ◽  
Marion Libouban ◽  
Maho Nagasawa ◽  
...  
Keyword(s):  
Cell Survival ◽  
Target Genes ◽  
Plasmacytoid Dendritic Cell ◽  
Critical Role ◽  
Type I Interferons ◽  
Transcriptional Level ◽  
Type I ◽  
Direct Target Gene ◽  
Antiapoptotic Gene ◽  
And Function

Plasmacytoid dendritic cells (pDCs) selectively express Toll-like receptor (TLR)–7 and TLR-9, which allow them to rapidly secrete massive amounts of type I interferons after sensing nucleic acids derived from viruses or bacteria. It is not completely understood how development and function of pDCs are controlled at the transcriptional level. One of the main factors driving pDC development is the ETS factor Spi-B, but little is known about its target genes. Here we demonstrate that Spi-B is crucial for the differentiation of hematopoietic progenitor cells into pDCs by controlling survival of pDCs and its progenitors. In search for Spi-B target genes, we identified the antiapoptotic gene Bcl2-A1 as a specific and direct target gene, thereby consolidating the critical role of Spi-B in cell survival.

Involvement of Receptor-Bound Protein Methyltransferase PRMT1 in Antiviral and Antiproliferative Effects of Type I Interferons

1999 ◽  
Vol 19 (2) ◽  
pp. 189-195 ◽  
Author(s):  
Laura Altschuler ◽  
Jae-Oh Wook ◽  
Dalia Gurari ◽  
Judith Chebath ◽  
Michel Revel
Keyword(s):  
Type I Interferons ◽  
Type I ◽  
Antiproliferative Effects ◽  
Protein Methyltransferase

Interferon-α and -β inhibit the in vitro differentiation of immunocompetent human dendritic cells from CD14+ precursors

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 210-217 ◽  
Author(s):  
Bradford L. McRae ◽  
Taro Nagai ◽  
Roshanak Tolouei Semnani ◽  
Jean Maguire van Seventer ◽  
Gijs A. van Seventer
Keyword(s):  
T Cell ◽  
Type I Interferons ◽  
Interferon Α ◽  
Type I ◽  
Cell Secretion ◽  
Gm Csf ◽  
Th Cell ◽  
Acquired Immune Responses ◽  
And Function

Abstract Dendritic cell (DC) precursors and immature DC reside in epithelium where they encounter pathogens and cytokines, which stimulate their differentiation. We hypothesized that type-I interferons (IFN- and -β), cytokines that are produced early in the innate immune response against viruses and some bacteria, may influence DC differentiation and function. To examine this possibility, we used an in vitro model of DC differentiation in which initial culture of human CD14+monocytes with granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 generates immature DC, and subsequent culture with tumor necrosis factor (TNF)- drives the final development into mature DC. We found in this model that IFN-/β, added from the initiation of the culture on, significantly reduced the survival and altered the morphology and differentiation of DC. TNF-–dependent maturation of IFN-β–treated immature DC led to cells with reduced expression of CD1a, CD40, CD54, and CD80 when compared with mature DC controls. IFN-/β–treated DC further had a reduced capacity to induce naive Th-cell proliferation through allostimulation or anti-CD3 monoclonal antibody stimulation. In addition, IFN-/β–treated DC secreted less IL-12 upon stimulation with Staphylococcus aureus Cowan strain or with CD4+ T cells, and this decrease correlated directly with their inability to support CD4+ T-cell secretion of IFN-γ, even though T-cell lymphotoxin production was unaffected. These findings indicate that type-I IFNs can influence the generation of acquired immune responses by modifying T-helper cell differentiation through the regulation of DC differentiation and function.

scholarly journals Infection-induced type I interferons critically modulate the homeostasis and function of CD8+ naïve T cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mladen Jergović ◽  
Christopher P. Coplen ◽  
Jennifer L. Uhrlaub ◽  
David G. Besselsen ◽  
Shu Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
West Nile Virus ◽  
Lymph Nodes ◽  
Mhc Class I ◽  
Type I Interferons ◽  
Type I ◽  
Tcr Signaling ◽  
Term Survival ◽  
And Function

AbstractNaïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy.

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