Protein Kinase R Regulates Double-Stranded RNA Induction of TNF-α But Not IL-1β mRNA in Human Epithelial Cells

Meusel, Tiffany R.; Kehoe, Kelly E.; Imani, Farhad

doi:10.4049/jimmunol.168.12.6429

Cited by 45 publications

(32 citation statements)

References 65 publications

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“…dsRNA is produced by most viruses during replication which recognizes the TLR3 on the cell membrane, upon binding and activation of the TLR3, dsRNA activates the NFκB pathway [47]. It is also known that dsRNA is closely associated with the interferon (IFN) system in host defense [48] and innate cytokine induction in lung epithelial cells [22,27]. It is interesting to find that after initial recognition of the pathogen by the receptors on the cells membrane, the signaling pathways activated by the virus and bacteria merges and cross-talk between the pathways occurred [49,50].…”

Section: Discussionmentioning

confidence: 99%

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Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

Limmon

Imani

et al. 2009

Biochimie

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Lactoferrin (LF) is a multifunctional protein. While its functions and mechanism of actions are actively being investigated, the cellular signals that regulate LF expression have not been as explored. We have previously demonstrated that LF is upregulated by estrogen in reproductive system. In this study, we show that the expression of LF was stimulated by bacterial lipopolysaccharide (LPS) and double-stranded RNA (dsRNA) in normal mouse mammalian HC-11 cells. When cells were exposed to either LPS or dsRNA, the mRNA and protein of LF were increased in a dose-and time-dependent manner, yet the kinetics of LF induction by dsRNA or LPS was different. The LPS and dsRNAinduced LF was mainly released into the culture medium where it blocked TNF-α production in exposed cells. We explored the mechanisms of LF induction by LPS and dsRNA using specific inhibitors and found that the induction could be attenuated by inhibitors to PKC, NF-kB, p38 and JNK, but not by an inhibitor to PKA. Interestingly, ERK inhibitor was effective against dsRNA but not against LPS induction of LF. These data suggest that LF was induced by LPS and dsRNA through PKC, NF-kB and MAPK pathways which in turn plays an inhibitory role in the continuation of innate inflammation.

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Section: Discussionmentioning

confidence: 99%

“…Addition of LPS or dsRNA to the cells rapidly induces phosphorylation of mitogen-activated protein kinase (MAPK) pathways, p38 and c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK). In addition, LPS and dsRNA signaling leads to downstream NF-kB activation in several cell lines [24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

Limmon

Imani

et al. 2009

Biochimie

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“…Because rotavirus is a dsRNA virus and dsRNA activates cytokine expression in retinal pigment and lung epithelia (17)(18)(19)38), dsRNA seemed a strong candidate to be a viral activator of gut epithelial cells. To investigate this notion, we stimulated T84 intestinal epithelial cells with a range of doses of synthetic dsRNA (poly(I:C) 2-100 g/ml) and measured changes in epithelial gene expression.…”

Section: Poly(i:c) Induces Changes In Epithelial Gene Expressionmentioning

confidence: 99%

“…Based on the emerging paradigm that epithelial sensing of bacteria is largely based on a series of intracellular and extracellular pattern recognition receptors (13,14), we reasoned that epithelia may also have receptors capable of directly recognizing viral products. As rotavirus is a nonenveloped, 11-segmented dsRNA virus (15,16) and several epithelial cell types (e.g., retinal pigment, lung) have been observed to respond to dsRNA (17)(18)(19), this seemed an especially likely molecule to be promoting activation of intestinal epithelial gene expression in response to rotavirus. Thus, we sought to define the effects of dsRNA on gut epithelial gene expression using a well-defined polarized model system.…”

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confidence: 99%

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

Vijay‐Kumar

Gentsch

Kaiser

et al. 2005

The Journal of Immunology

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As sentinels of host defense, intestinal epithelial cells respond to the viral pathogen rotavirus by activating a gene expression that promotes immune cell recruitment and activation. We hypothesized that epithelial sensing of rotavirus might target dsRNA, which can be detected by TLR3 or protein kinase R (PKR). Accordingly, we observed that synthetic dsRNA, polyinosinic acid:cytidylic acid (poly(I:C)), potently induced gene remodeling in model intestinal epithelia with the specific pattern of expressed genes, including both classic proinflammatory genes (e.g., IL-8), as well as genes that are classically activated in virus-infected cells (e.g., IFN-responsive genes). Poly(I:C)-induced IL-8 was concentration dependent (2–100 μg/ml) and displayed slower kinetics compared with IL-8 induced by bacterial flagellin (ET50 ∼24 vs 8 h poly(I:C) vs flagellin, respectively). Although model epithelia expressed detectable TLR3 mRNA, neither TLR3-neutralizing Abs nor chloroquine, which blocks activation of intracellular TLR3, attenuated epithelial responses to poly(I:C). Conversely, poly(I:C)-induced phosphorylation of PKR and inhibitors of PKR, 2-aminopurine and adenine, ablated poly(I:C)-induced gene expression but had no effect on gene expression induced by flagellin, thus suggesting that intestinal epithelial cell detection of dsRNA relies on PKR. Consistent with poly(I:C) detection by an intracellular molecule such as PKR, we observed that both uptake of and responses to poly(I:C) were polarized to the basolateral side. Lastly, we observed that the pattern of pharmacologic inhibition of responses to poly(I:C) was identical to that seen in response to infection by live rotavirus, indicating a potentially important role for PKR in activating intestinal epithelial gene expression in rotavirus infection.

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“…E3 is a double-stranded RNA binding protein that inhibits the activation of protein kinase R (PKR) (18), a multifunctional antiviral protein (47). PKR inhibits viral replication by blocking both host and viral protein synthesis and regulates cytokine expression (47)(48)(49). Therefore, the ability of E3 to inhibit PKR activation is crucial for maintaining the cellular translation machinery (50).…”

Section: Discussionmentioning

confidence: 99%

Identification of 10 Cowpox Virus Proteins That Are Necessary for Induction of Hemorrhagic Lesions (Red Pocks) on Chorioallantoic Membranes

Zhang

Zikos

Tamošiūnaitė³

et al. 2014

J Virol

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Cowpox viruses (CPXV) cause hemorrhagic lesions ("red pocks") on infected chorioallantoic membranes (CAM) of embryonated chicken eggs, while most other members of the genus Orthopoxvirus produce nonhemorrhagic lesions ("white pocks"). Cytokine response modifier A (CrmA) of CPXV strain Brighton Red (BR) is necessary but not sufficient for the induction of red pocks. To identify additional viral proteins involved in the induction of hemorrhagic lesions, a library of single-gene CPXV knockout mutants was screened. We identified 10 proteins that are required for the formation of hemorrhagic lesions, which are encoded by CPXV060, CPXV064, CPXV068, CPXV069, CPXV074, CPXV136, CPXV168, CPXV169, CPXV172, and CPXV199. The genes are the homologues of F12L, F15L, E2L, E3L, E8R, A4L, A33R, A34R, A36R, and B5R of vaccinia virus (VACV). Mutants with deletions in CPXV060, CPXV168, CPXV169, CPXV172, or CPXV199 induced white pocks with a comet-like shape on the CAM. The homologues of these five genes in VACV encode proteins that are involved in the production of extracellular enveloped viruses (EEV) and the repulsion of superinfecting virions by actin tails. The homologue of CPXV068 in VACV is also involved in EEV production but is not related to actin tail induction. The other genes encode immunomodulatory proteins (CPXV069 and crmA) and viral core proteins (CPXV074 and CPXV136), and the function of the product of CPXV064 is unknown. IMPORTANCE It has been known for a long time that cowpox virus induces hemorrhagic lesions on chicken CAM, while most of the other orthopoxviruses produce nonhemorrhagic lesions. Although cowpox virusCrmA has been proved to be responsible for the hemorrhagic phenotype, other proteins causing this phenotype remain unknown. Recently, we generated a complete single-gene knockout bacterial artificial chromosome (BAC) library of cowpox virus Brighton strain. Out of 183 knockout BAC clones, 109 knockout viruses were reconstituted. The knockout library makes possible high-throughput screening for studying poxvirus replication and pathogenesis. In this study, we screened all 109 single-gene knockout viruses and identified 10 proteins necessary for inducing hemorrhagic lesions. The identification of these genes gives a new perspective for studying the hemorrhagic phenotype and may give a better understanding of poxvirus virulence.

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Protein Kinase R Regulates Double-Stranded RNA Induction of TNF-α But Not IL-1β mRNA in Human Epithelial Cells

Cited by 45 publications

References 65 publications

Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

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

Identification of 10 Cowpox Virus Proteins That Are Necessary for Induction of Hemorrhagic Lesions (Red Pocks) on Chorioallantoic Membranes

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