Protein Kinase R Mediates Intestinal Epithelial Gene Remodeling in Response to Double-Stranded RNA and Live Rotavirus

Vijay‐Kumar, Matam; Gentsch, Jon R.; Kaiser, William J.; Borregaard, Niels; Offermann, Margaret K.; Neish, Andrew S.; Gewirtz, Andrew T.

doi:10.4049/jimmunol.174.10.6322

Cited by 47 publications

(42 citation statements)

References 60 publications

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“…Although PKR signaling through NF-B may have a role in the poly(I:C) stimulated IL-8 response, those studies did not assess type I IFN expression. Moreover, the specificity of inhibition by 2-AP for PKR in those studies was not confirmed using specific genetic approaches (46). Whereas, 2-AP inhibited poly(I:C) stimulated type I IFN production, we also found that 2-AP inhibition was not specific for PKR Thus, in addition to PKR, 2-AP also inhibited STAT1 and IRF3 phosphorylation that are key in the activation of the IFN pathway (data not shown), and others have previously reported that 2-AP inhibited leptin induced STAT3, ERK, and JNK activation, independently of PKR (47).…”

Section: Discussionmentioning

confidence: 83%

“…Poly(I:C) was reported to up-regulate IL-8 mRNA in the human IEC line T84 in the absence of an added membrane permeant, by signaling through PKR as determined using pharmacological inhibitors of PKR (e.g., 2-AP) (46). Although PKR signaling through NF-B may have a role in the poly(I:C) stimulated IL-8 response, those studies did not assess type I IFN expression.…”

Section: Discussionmentioning

confidence: 99%

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Activation of Innate Immune Defense Mechanisms by Signaling through RIG-I/IPS-1 in Intestinal Epithelial Cells

Hirata¹,

Broquet²,

Menchén³

et al. 2007

The Journal of Immunology

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Intestinal epithelial cells (IECs) are a first line of defense against microbial pathogens that enter the host through the intestinal tract. Moreover, viral pathogens that infect the host via the intestinal epithelium are an important cause of morbidity and mortality. However, the mechanisms by which viral pathogens activate antiviral defense mechanisms in IECs are largely unknown. The synthetic dsRNA analog polyinosinic-polycytidylic acid and infection with live virus were used to probe the molecules that are activated and the mechanisms of signaling in virus-infected human IECs. Polyinosinic-polycytidylic acid activated IFN regulatory factor 3 dimerization and phosphorylation, increased activity of the IFN-stimulated response element, induced a significant increase in IFN-β mRNA transcripts and IFN-β secretion, and up-regulated the expression of IFN-regulated genes in IECs. Those responses were dependent upon activation of the dsRNA binding protein retinoic acid inducible gene I (RIG-I) and the RIG-I interacting protein IFN promoter stimulator-1, but not on dsRNA-activated protein kinase or TLR3, which also were expressed by IECs. Virus replication and virus-induced cell death increased in IECs in which RIG-I was silenced, consistent with the importance of the RIG-I signaling pathway in IEC antiviral innate immune defense mechanisms.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Activation of Innate Immune Defense Mechanisms by Signaling through RIG-I/IPS-1 in Intestinal Epithelial Cells

Hirata¹,

Broquet²,

Menchén³

et al. 2007

The Journal of Immunology

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“…Although NF-B activation following stimulation with poly(I:C) has also been observed in other cells of the epithelial lineage, such as in human respiratory (46 -49), reproductive (50), uterine (51), and intestinal (52,53) epithelium, this has been generally attributed to the expression and function of TLR3. Apart from TLR3-dependent NF-B activation after dsRNA stimulation, IRF3 signals resulting in type I IFN production have also been demonstrated as a consequence of TLR3 ligand binding in normal human keratinocytes using a model that did not integrate the combined function of PKR, RIG-I (54), or MDA5 (45).…”

Section: Discussionmentioning

confidence: 99%

Double-Stranded RNA Induces an Antiviral Defense Status in Epidermal Keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-Mediated Differential Signaling

Kalali

Köllisch

Mages

et al. 2008

The Journal of Immunology

163

139

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Emerging evidence suggests an important role for human epidermal keratinocytes in innate immune mechanisms against bacterial and viral skin infections. The proinflammatory effect of viral infections can be mimicked by double-stranded RNA (dsRNA). Herein, we demonstrate that keratinocytes express all known dsRNA sensing receptors at a constitutive and inducible level, and that they use several downstream signaling pathways leading to a broad pattern of gene expression, not only proinflammatory and immune response genes under the control of NF-B, but also genes under transcriptional control of IRF3. As a consequence, dsRNA, a stimulus for TLR3, protein kinase R (PKR), and the RNA helicases retinoic acid-inducible gene I (RIG-I) and MDA5, induces a status of antiviral defense in keratinocytes. Using inhibitors for the various dsRNA signaling pathways and specific small interfering RNA for TLR3, RIG-I, and MDA5, we demonstrated that in human keratinocytes, TLR3 seems to be necessary for NF-B but not for IRF3 activation, whereas RIG-I and MDA5 are crucial for IRF3 activation. PKR is essential for the dsRNA response in both signaling pathways and thus represents the central antiviral receptor for dsRNA stimulation. Moreover, human keratinocytes up-regulate TLR7, the receptor for single-stranded RNA, in response to stimulation with dsRNA, which renders keratinocytes functionally responsive to the TLR7 agonist gardiquimod, a member of the imidazoquinoline antiviral immune response modifier family. Thus, in addition to building a physical barrier against infectious pathogens, keratinocytes are specially equipped with a full antiviral defense program that enables them to efficiently target viral infections of the skin.

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“…However, Lcn2 was originally discovered as an early response gene, induced to high levels in growth-arrested murine kidney cells following infection with simian virus 40 (SV40) (30). More recently, rhesus rotavirus infection of human epithelial cells (31) and human papillomavirus infection of keratinocytes (32) were also shown to induce Lcn2. Despite these associations of Lcn2 with viral infection of cells in vitro, little is known concerning the regulation of Lcn2 gene expression and the function of this factor in the host response to viral infection in vivo.…”

Section: Discussionmentioning

confidence: 99%

The Bacteriostatic Protein Lipocalin 2 Is Induced in the Central Nervous System of Mice with West Nile Virus Encephalitis

Noçon

Terry

et al. 2014

J Virol

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Lipocalin 2 (Lcn2) is a bacteriostatic factor produced during the innate immune response to bacterial infection. Whether Lcn2 has a function in viral infection is unknown. We investigated the regulation and function of Lcn2 in the central nervous system (CNS) of mice during West Nile virus (WNV) encephalitis. Lcn2 mRNA and protein were induced in the brain by day 5, and this induction increased further by day 7 postinfection but was delayed compared with the induction of the toll-like receptor 3 (TLR3) gene, retinoic acid-inducible gene 1 (RIG-I), and melanoma differentiation-associated protein 5 (MDA5) gene. The Lcn2 mRNA and protein were both found at high levels in the choroid plexus, vascular endothelium, macrophage/microglia, and astrocytes. However, some neuronal subsets contained Lcn2 protein but no detectable mRNA. In Lcn2 knockout (KO) mice, with the exception of CXC motif chemokine 5 (CXCL5), which was significantly more downregulated than in wild-type (WT) mice, expression levels of a number of other host response genes were similar in the two genotypes. The brain from Lcn2 and WT mice with WNV encephalitis contained similar numbers of infiltrating macrophages, granulocytes, and T cells. Lcn2 KO and WT mice had no significant difference in tissue viral loads or survival after infection with different doses of WNV. We conclude that Lcn2 gene expression is induced to high levels in a time-dependent fashion in a variety of cells and regions of the CNS of mice with WNV encephalitis. The function of Lcn2 in the host response to WNV infection remains largely unknown, but our data indicate that it is dispensable as an antiviral or immunoregulatory factor in WNV encephalitis.

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Protein Kinase R Mediates Intestinal Epithelial Gene Remodeling in Response to Double-Stranded RNA and Live Rotavirus

Cited by 47 publications

References 60 publications

Activation of Innate Immune Defense Mechanisms by Signaling through RIG-I/IPS-1 in Intestinal Epithelial Cells

Activation of Innate Immune Defense Mechanisms by Signaling through RIG-I/IPS-1 in Intestinal Epithelial Cells

Double-Stranded RNA Induces an Antiviral Defense Status in Epidermal Keratinocytes through TLR3-, PKR-, and MDA5/RIG-I-Mediated Differential Signaling

The Bacteriostatic Protein Lipocalin 2 Is Induced in the Central Nervous System of Mice with West Nile Virus Encephalitis

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