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Lymphotoxin β receptor signaling induces IL-8 production in human bronchial epithelial cells.

Mikami Y, Matsuzaki H, Horie M, Noguchi S, Jo T, Narumoto O, Kohyama T, Takizawa H, Nagase T, Yamauchi Y - PLoS ONE (2014)

Bottom Line: LIGHT also induced luciferase activity of NF-κB response element, but not of activator protein-1 or serum response element.Specific inhibitors of phosphorylation of extracellular signal-regulated kinase (Erk) and that of inhibitor κB attenuated IL-8 production, suggesting that LIGHT-LTβR signaling induces IL-8 production via the Erk and NF-κB pathways.LIGHT, via LTβR signaling, may contribute to exacerbation of airway neutrophilic inflammation through cytokine and chemokine production by bronchial epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

ABSTRACT
Asthma-related mortality has been decreasing due to inhaled corticosteroid use, but severe asthma remains a major clinical problem. One characteristic of severe asthma is resistance to steroid therapy, which is related to neutrophilic inflammation. Recently, the tumor necrosis factor superfamily member (TNFSF) 14/LIGHT has been recognized as a key mediator in severe asthmatic airway inflammation. However, the profiles and intracellular mechanisms of cytokine/chemokine production induced in cells by LIGHT are poorly understood. We aimed to elucidate the molecular mechanism of LIGHT-induced cytokine/chemokine production by bronchial epithelial cells. Human bronchial epithelial cells express lymphotoxin β receptor (LTβR), but not herpesvirus entry mediator, which are receptors for LIGHT. LIGHT induced various cytokines/chemokines, such as interleukin (IL)-6, oncostatin M, monocyte chemotactic protein-1, growth-regulated protein α and IL-8. Specific siRNA for LTβR attenuated IL-6 and IL-8 production by BEAS-2B and normal human bronchial epithelial cells. LIGHT activated intracellular signaling, such as mitogen-activated protein kinase and nuclear factor-κB (NF-κB) signaling. LIGHT also induced luciferase activity of NF-κB response element, but not of activator protein-1 or serum response element. Specific inhibitors of phosphorylation of extracellular signal-regulated kinase (Erk) and that of inhibitor κB attenuated IL-8 production, suggesting that LIGHT-LTβR signaling induces IL-8 production via the Erk and NF-κB pathways. LIGHT, via LTβR signaling, may contribute to exacerbation of airway neutrophilic inflammation through cytokine and chemokine production by bronchial epithelial cells.

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Schematic summary of how LTβR signal transduction induces IL-8 expression in human bronchial epithelial cells.LIGHT binding to LTβR may induce Erk1/2 or IκBα phosphorylation, which in turn induces NF-κB activation, and ultimately causes IL-8 release from the cells.
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pone-0114791-g009: Schematic summary of how LTβR signal transduction induces IL-8 expression in human bronchial epithelial cells.LIGHT binding to LTβR may induce Erk1/2 or IκBα phosphorylation, which in turn induces NF-κB activation, and ultimately causes IL-8 release from the cells.

Mentions: Some transcriptional factors, such as NF-κB and AP-1, were reported to regulate IL-8 expression [34]. It is thought that LIGHT induces IL-8 production through NF-κB release [35], [36]. Our results showed that U0126 completely inhibited IL-8 production, so we investigated the possibility that the Erk1/2 pathway activated the NF-κB pathway. Indeed, U0126 partially attenuated LIGHT-induced luciferase activity of NF-κB response element, but it did not inhibit NF-κB release and translocation to the nucleus. As shown in Fig. 9, these results suggested that there were two pathways by which LIGHT induced IL-8: (1) via Erk1/2 and (2) directly via NF-κB. Although the mechanism by which Erk1/2 induces IL-8 gene expression is not clear, Erk2 (p44/42 MAPK) was reported to phosphorylate Elk-1 and activates SRE, leading to induction of c-fos, a component of AP-1 [37]. The AP-1 binding element is present in the promoter region of the IL-8 gene, and AP-1, a complex of c-fos and c-jun or jun B, plays an important role in transcriptional regulation of IL-8 mRNA expression [38]–[40]. On the other hand, it has been considered that LIGHT induces two types of NF-κB pathway. One is degradation of IκBα to release p50/RelA and p50/c-Rel heterodimers via TNF receptor-associated factors [41]. The other is involvement of LTβR in NF-κB-inducing kinase activation to promote p100 processing [42].


Lymphotoxin β receptor signaling induces IL-8 production in human bronchial epithelial cells.

Mikami Y, Matsuzaki H, Horie M, Noguchi S, Jo T, Narumoto O, Kohyama T, Takizawa H, Nagase T, Yamauchi Y - PLoS ONE (2014)

Schematic summary of how LTβR signal transduction induces IL-8 expression in human bronchial epithelial cells.LIGHT binding to LTβR may induce Erk1/2 or IκBα phosphorylation, which in turn induces NF-κB activation, and ultimately causes IL-8 release from the cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263477&req=5

pone-0114791-g009: Schematic summary of how LTβR signal transduction induces IL-8 expression in human bronchial epithelial cells.LIGHT binding to LTβR may induce Erk1/2 or IκBα phosphorylation, which in turn induces NF-κB activation, and ultimately causes IL-8 release from the cells.
Mentions: Some transcriptional factors, such as NF-κB and AP-1, were reported to regulate IL-8 expression [34]. It is thought that LIGHT induces IL-8 production through NF-κB release [35], [36]. Our results showed that U0126 completely inhibited IL-8 production, so we investigated the possibility that the Erk1/2 pathway activated the NF-κB pathway. Indeed, U0126 partially attenuated LIGHT-induced luciferase activity of NF-κB response element, but it did not inhibit NF-κB release and translocation to the nucleus. As shown in Fig. 9, these results suggested that there were two pathways by which LIGHT induced IL-8: (1) via Erk1/2 and (2) directly via NF-κB. Although the mechanism by which Erk1/2 induces IL-8 gene expression is not clear, Erk2 (p44/42 MAPK) was reported to phosphorylate Elk-1 and activates SRE, leading to induction of c-fos, a component of AP-1 [37]. The AP-1 binding element is present in the promoter region of the IL-8 gene, and AP-1, a complex of c-fos and c-jun or jun B, plays an important role in transcriptional regulation of IL-8 mRNA expression [38]–[40]. On the other hand, it has been considered that LIGHT induces two types of NF-κB pathway. One is degradation of IκBα to release p50/RelA and p50/c-Rel heterodimers via TNF receptor-associated factors [41]. The other is involvement of LTβR in NF-κB-inducing kinase activation to promote p100 processing [42].

Bottom Line: LIGHT also induced luciferase activity of NF-κB response element, but not of activator protein-1 or serum response element.Specific inhibitors of phosphorylation of extracellular signal-regulated kinase (Erk) and that of inhibitor κB attenuated IL-8 production, suggesting that LIGHT-LTβR signaling induces IL-8 production via the Erk and NF-κB pathways.LIGHT, via LTβR signaling, may contribute to exacerbation of airway neutrophilic inflammation through cytokine and chemokine production by bronchial epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

ABSTRACT
Asthma-related mortality has been decreasing due to inhaled corticosteroid use, but severe asthma remains a major clinical problem. One characteristic of severe asthma is resistance to steroid therapy, which is related to neutrophilic inflammation. Recently, the tumor necrosis factor superfamily member (TNFSF) 14/LIGHT has been recognized as a key mediator in severe asthmatic airway inflammation. However, the profiles and intracellular mechanisms of cytokine/chemokine production induced in cells by LIGHT are poorly understood. We aimed to elucidate the molecular mechanism of LIGHT-induced cytokine/chemokine production by bronchial epithelial cells. Human bronchial epithelial cells express lymphotoxin β receptor (LTβR), but not herpesvirus entry mediator, which are receptors for LIGHT. LIGHT induced various cytokines/chemokines, such as interleukin (IL)-6, oncostatin M, monocyte chemotactic protein-1, growth-regulated protein α and IL-8. Specific siRNA for LTβR attenuated IL-6 and IL-8 production by BEAS-2B and normal human bronchial epithelial cells. LIGHT activated intracellular signaling, such as mitogen-activated protein kinase and nuclear factor-κB (NF-κB) signaling. LIGHT also induced luciferase activity of NF-κB response element, but not of activator protein-1 or serum response element. Specific inhibitors of phosphorylation of extracellular signal-regulated kinase (Erk) and that of inhibitor κB attenuated IL-8 production, suggesting that LIGHT-LTβR signaling induces IL-8 production via the Erk and NF-κB pathways. LIGHT, via LTβR signaling, may contribute to exacerbation of airway neutrophilic inflammation through cytokine and chemokine production by bronchial epithelial cells.

Show MeSH
Related in: MedlinePlus