Double-Stranded RNA Induces the Synthesis of Specific Chemokines by Bronchial Epithelial Cells

Gern, James E.; French, Delores A.; Grindle, Kristine A.; Brockman-Schneider, Rebecca; Konno, Satoshi; Busse, William W.

doi:10.1165/rcmb.2002-0055oc

Cited by 129 publications

(115 citation statements)

References 26 publications

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“…Our findings also suggest that to some extent dsRNA and influenza A virus use different signaling mechanisms to induce inflammatory epithelial responses; dsRNA triggers IL-8 secretion via at least the signal-transducing molecules ERK, p38, and PI3K/Akt, whereas RANTES release appears to be mainly dependent on a PI3K/Akt activation. These results are in agreement with recent work showing p38-dependent production of IL-8 but not of RANTES in lung epithelial cells following dsRNA treatment (15). Also, the role of the PI3K-Akt pathway in TLR3-mediated gene induction was robustly supported by Sarkar et al (36) in a very recent study.…”

Section: Tlr3 Signaling and Respiratory Epithelial Cell Activationsupporting

confidence: 92%

Involvement of Toll-like Receptor 3 in the Immune Response of Lung Epithelial Cells to Double-stranded RNA and Influenza A Virus

Guillot

Goffic

Bloch

et al. 2005

Journal of Biological Chemistry

607

506

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Influenza A is a highly contagious single-stranded RNA virus that infects both the upper and lower respiratory tracts of humans. The host innate immune Tolllike receptor (TLR) 3 was shown previously in cells of myeloid origin to recognize the viral replicative, intermediate double-stranded RNA (dsRNA). Thus, dsRNA may be critical for the outcome of the infection. Here we first compared the activation triggered by either influenza A virus or dsRNA in pulmonary epithelial cells. We established that TLR3 is constitutively expressed in human alveolar and bronchial epithelial cells, and we describe its intracellular localization. Expression of TLR3 was positively regulated by the influenza A virus and by dsRNA but not by other inflammatory mediators, including bacterial lipopolysaccharide, the cytokines tumor necrosis factor-␣ and interleukin (IL)-1␤, and the protein kinase C activator phorbol 12-myristate 13-acetate. We also demonstrated that TLR3 contributes directly to the immune response of respiratory epithelial cells to influenza A virus and dsRNA, and we propose a molecular mechanism by which these stimuli induce epithelial cell activation. This model involves mitogen-activated protein kinases, phosphatidylinositol 3-kinase/ Akt signaling, and the TLR3-associated adaptor molecule TRIF but not MyD88-dependent activation of the transcription factors NF-B or interferon regulatory factor/interferon-sensitive response-element pathways. Ultimately, this signal transduction elicits an epithelial response that includes the secretion of the cytokines IL-8, IL-6, RANTES (regulated on activation normal T cell expressed and secreted), and interferon-␤ and the up-regulation of the major adhesion molecule ICAM-1.

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Section: Tlr3 Signaling and Respiratory Epithelial Cell Activationsupporting

confidence: 92%

Involvement of Toll-like Receptor 3 in the Immune Response of Lung Epithelial Cells to Double-stranded RNA and Influenza A Virus

Guillot

Goffic

Bloch

et al. 2005

Journal of Biological Chemistry

607

506

View full text Add to dashboard Cite

show abstract

“…Expression was observed in our mice early in infection and was maximal at day 8 when strong immunoreactivity in epithelial cells lining the airways and in mononuclear cells was obvious. Pulmonary epithelial cells express TLR3 (46,68) and PKR (46,68,69). S100A8 is up-regulated in bronchial epithelial cells by LPS (3) and S100A8/S100A9 is expressed in tracheal epithelial cells from patients with cystic fibrosis (70).…”

Section: Discussionmentioning

confidence: 99%

IL-10-Dependent S100A8 Gene Induction in Monocytes/Macrophages by Double-Stranded RNA

Endoh¹,

Chung²,

Clark

et al. 2009

The Journal of Immunology

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The S100 calcium-binding proteins S100A8 and S100A9 are elevated systemically in patients with viral infections. The S100A8-S100A9 complex facilitated viral replication in human CD4+ T lymphocytes latently infected with HIV-1- and S100A8-induced HIV-1 transcriptional activity. Mechanisms inducing the S100 genes and the potential source of these proteins following viral activation are unknown. In this study, we show that S100A8 was induced in murine macrophages, and S100A8 and S100A9 in human monocytes and macrophages, by polyinosinic:polycytidylic acid, a dsRNA mimetic. Induction was at the transcriptional level and was IL-10 dependent. Similar to LPS-induced S100A8, induction by dsRNA was dependent on p38 and ERK MAPK. Protein kinase R (PKR) mediates antiviral defense and participates in MyD88-dependent/independent signaling triggered by TLR4 or TLR3. Like IL-10, S100 induction by polyinosinic:polycytidylic acid and by LPS was inhibited by the specific PKR inhibitor 2-aminopurine, indicating a novel IL-10, PKR-dependent pathway. Other mediators such as IFN-β, which synergized with dsRNA, may also be involved. C/EBPβ bound the defined promoter region in response to dsRNA. S100A8 was expressed in lungs of mice infected with influenza virus and was maximal at day 8 with strong immunoreactivity in epithelial cells lining the airways and in mononuclear cells and declined early in the recovery phase, implying down-regulation by mediator(s) up-regulated during resolution of the infection. IL-10 is implicated in viral persistence. Since S100A8/S100A9 levels are likely to be maintained in conditions where IL-10 is raised, these proteins may contribute to viral persistence in patients infected by some RNA viruses.

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“…Virus infection and dsRNA have been shown to activate MAPK pathways in different cell types via PKR-dependent and -independent mechanisms and MAPK activation has been implicated in the regulation of inflammatory gene expression (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). We have shown that dsRNA-and EMCV infection stimulates ERK activation and ERK-dependent regulation of IL-1 expression (19, 29 -31).…”

Section: Role Of Mapk In the Regulationmentioning

confidence: 99%

Role of MAPK in the Regulation of Double-Stranded RNA- and Encephalomyocarditis Virus-Induced Cyclooxygenase-2 Expression by Macrophages

Steer

Moran

Christmann

et al. 2006

The Journal of Immunology

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In response to virus infection or treatment with dsRNA, macrophages express the inducible form of cyclooxygenase-2 (COX-2) and produce proinflammatory prostaglandins. Recently, we have shown that NF-κB is required for encephalomyocarditis virus (EMCV)- and dsRNA-stimulated COX-2 expression in mouse macrophages. The dsRNA-dependent protein kinase R is not required for EMCV-stimulated COX-2 expression, suggesting the presence of protein kinase R-independent pathways in the regulation of this antiviral gene. In this study, the role of MAPK in the regulation of macrophage expression of cyclooxygenase-2 (COX)-2 in response to EMCV infection was examined. Treatment of mouse macrophages or RAW-264.7 cells with dsRNA or infection with EMCV stimulates the rapid activation of the MAPKs p38, JNK, and ERK. Inhibition of p38 and JNK activity results in attenuation while ERK inhibition does not modulate dsRNA- and EMCV-induced COX-2 expression and PGE2 production by macrophages. JNK and p38 appear to selectively regulate COX-2 expression, as inhibition of either kinase fails to prevent dsRNA- or EMCV-stimulated inducible NO synthase expression by macrophages. Using macrophages isolated from TLR3-deficient mice, we show that p38 and JNK activation and COX-2 expression in response to EMCV or poly(IC) does not require the presence the dsRNA receptor TLR3. These findings support a role for p38 and JNK in the selective regulation of COX-2 expression by macrophages in response to virus infection.

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Double-Stranded RNA Induces the Synthesis of Specific Chemokines by Bronchial Epithelial Cells

Cited by 129 publications

References 26 publications

Involvement of Toll-like Receptor 3 in the Immune Response of Lung Epithelial Cells to Double-stranded RNA and Influenza A Virus

Involvement of Toll-like Receptor 3 in the Immune Response of Lung Epithelial Cells to Double-stranded RNA and Influenza A Virus

IL-10-Dependent S100A8 Gene Induction in Monocytes/Macrophages by Double-Stranded RNA

Role of MAPK in the Regulation of Double-Stranded RNA- and Encephalomyocarditis Virus-Induced Cyclooxygenase-2 Expression by Macrophages

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