Synthetic double‐stranded RNA induces multiple genes related to inflammation through Toll‐like receptor 3 depending on NF‐κB and/or IRF‐3 in airway epithelial cells

Matsukura, Satoshi; Kokubu, Fumio; Kurokawa, Masatsugu; Kawaguchi, Mio; Ieki, Koushi; Kuga, Hideki; Odaka, Miho; Suzuki, Shintaro; Watanabe, Shin; Takeuchi, Hiroko; Kasama, Tsuyoshi; Adachi, Mitsuru

doi:10.1111/j.1365-2222.2006.02530.x

Cited by 106 publications

(110 citation statements)

References 59 publications

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“…Although BAL eosinophilia peaked at 2 h after PGD 2 instillation and returned to baseline within 8 h in the IL-5-pretreated rats, it remained elevated for Ͼ8 h in the OVAexposed animals. These observations suggest that dsRNA induces the expression of another molecule(s), such as adhesion molecules (47), which augment and/or maintain the airway eosinophilia by interacting with PGD 2 .…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2/Prostaglandin D2/CRTH2 Pathway Mediates Double-Stranded RNA-Induced Enhancement of Allergic Airway Inflammation

Shiraishi

Asano

Niimi

et al. 2008

The Journal of Immunology

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Respiratory RNA viruses responsible for the common cold often worsen airway inflammation and bronchial responsiveness, two characteristic features of human asthma. We studied the effects of dsRNA, a nucleotide synthesized during viral replication, on airway inflammation and bronchial hyperresponsiveness in murine models of asthma. Intratracheal instillation of poly I:C, a synthetic dsRNA, increased the airway eosinophilia and enhanced bronchial hyperresponsiveness to methacholine in OVA-sensitized, exposed rats. These changes were associated with induction of cyclooxygenase-2 (COX-2) expression and COX-2-dependent PGD2 synthesis in the lungs, particularly in alveolar macrophages. The direct intratracheal instillation of PGD2 enhanced the eosinophilic inflammation in OVA-exposed animals, whereas pretreatment with a dual antagonist against the PGD2 receptor-(CRTH2) and the thromboxane A2 receptor, but not with a thromboxane A2 receptor-specific antagonist, nearly completely eliminated the dsRNA-induced worsening of airway inflammation and bronchial hyperresponsiveness. CRTH2-deficient mice had the same degree of allergen-induced airway eosinophilia as wild-type mice, but they did not exhibit a dsRNA-induced increase in eosinophil accumulation. Our data demonstrate that COX-2-dependent production of PGD2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenetic factors responsible for the dsRNA-induced enhancement of airway inflammation and responsiveness.

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Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2/Prostaglandin D2/CRTH2 Pathway Mediates Double-Stranded RNA-Induced Enhancement of Allergic Airway Inflammation

Shiraishi

Asano

Niimi

et al. 2008

The Journal of Immunology

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“…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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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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“…TLR2 also cooperates with lectin receptors, enabling recognition of the fungal cell wall component zymosan [14,15]. Doublestranded RNA and some synthetic RNA derivatives (polyinosilic-polycytidylic acid) are ligands for TLR3 [16,17]. The ultimate lipopolysaccharide receptor is TLR4 [18].…”

Section: Structure and Activationmentioning

confidence: 99%

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Wolska

Lech‐Marańda

Robak

2009

Cellular and Molecular Biology Letters

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Toll-like receptors (TLRs) have been described as major components of the innate immune system, recognizing the conserved molecular structures found in the large groups of pathogens called pathogen-associated molecular patterns (PAMPs). TLR expression is ubiquitous, from epithelial to immunocompetent cells. TLR ligation triggers several adapter proteins and downstream kinases, leading to the induction of key pro-inflammatory mediators but also anti-inflammatory and anti-tumor cytokines. The result of this activation goes beyond innate immunity to shape the adaptive responses against pathogens and tumor cells, and maintains host homeostasis via cell debris utilization. TLRs have already become potent targets in infectious disease treatment and vaccine therapy and in neoplastic disease treatment, due to their ability to enhance antigen presentation. However, some studies show the dual effect of TLR stimulation on malignant cells: they can be proapoptotic or promote survival under different conditions. It is therefore crucial to design further studies assessing the biology of these receptors in normal and transformed cells. The established role of TLRs in human disease therapy is based on TLR7 and TLR4 agonists, respectively for the novel treatment of some types of skin cancer and for the anti-hepatitis B virus vaccine. Some clinical trials involving TLR agonists as potent enhancers of the anti-tumor response in solid tumors have begun.

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Synthetic double‐stranded RNA induces multiple genes related to inflammation through Toll‐like receptor 3 depending on NF‐κB and/or IRF‐3 in airway epithelial cells

Abstract: TLR3 is expressed inside airway epithelial cells and transduces synthetic dsRNA signals. These signals may increase expression of inflammatory cytokines, chemokines and ICAM-1 through activation of transcription factors NF-kappaB and/or IRF3 in airway epithelial cells.

Cited by 106 publications

References 59 publications

Cyclooxygenase-2/Prostaglandin D2/CRTH2 Pathway Mediates Double-Stranded RNA-Induced Enhancement of Allergic Airway Inflammation

Cyclooxygenase-2/Prostaglandin D2/CRTH2 Pathway Mediates Double-Stranded RNA-Induced Enhancement of Allergic Airway Inflammation

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

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

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