Interleukin-26 Production in Human Primary Bronchial Epithelial Cells in Response to Viral Stimulation: Modulation by Th17 cytokines

Abstract

Interleukin (IL)-26 is abundant in human airways and this cytokine is involved in the local immune response to a bacterial stimulus in vivo. Specifically, local exposure to the toll-like receptor (TLR) 4 agonist endotoxin does increase IL-26 in human airways and this cytokine potentiates chemotactic responses in human neutrophils. In addition to T-helper (Th) 17 cells, alveolar macrophages can produce IL-26, but it remains unknown whether this cytokine can also be produced in the airway mucosa per se in response to a viral stimulus. Here, we evaluated whether this is the case using primary bronchial epithelial cells from the airway epithelium in vitro and explored the signaling mechanisms involved, including the modulatory effects of additional Th17 cytokines. Finally, we assessed IL-26 and its archetype signaling responses in healthy human airways in vivo. We found increased transcription and release of IL-26 protein after stimulation with the viral-related double stranded (ds) RNA polyinosinic-polycytidylic acid (poly-IC) and showed that this IL-26 release involved mitogen-activated protein (MAP) kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The release of IL-26 in response to a viral stimulus was modulated by additional Th17 cytokines. Moreover, there was transcription of IL26 mRNA and expression of the protein in epithelial cells of bronchial brush and tissue biopsies respectively after harvest in vivo. In addition, the extracellular IL-26 protein concentrations in bronchoalveolar lavage (BAL) samples did correlate with increased epithelial cell transcription of an archetype intracellular signaling molecule downstream of the IL-26-receptor complex, STAT1, in the bronchial brush biopsies. Thus, our study suggests that viral stimulation causes the production of IL-26 in lining epithelial cells of human airways, structural cells that constitute a critical immune barrier and that this production is modulated by Th17 cytokines.

Biological Effects of IL-26 on T Cell–Mediated Skin Inflammation, Including Psoriasis

“…While immunofluorescence staining of skin sections of hIL-26Tg mice indicated that IL-26 was produced by CD4-positive cells as well as other cell types, the cells involved may differ in the IMQ-induced psoriasis model from psoriasis patients (Figure 3b, 3d). In addition to Th17 cells, other IL-26eproducing cells have been identified recently (Che et al, 2014(Che et al, , 2017Corvaisier et al, 2012;Poli et al, 2017). In the skin lesions of psoriatic patients, IL-17 is produced not only from CD4 þ T cells, but also from CD8 þ T cells and gd T cells (Golden et al, 2013;Matos et al, 2017).…”

Enhanced local production of IL-26 in uncontrolled compared with controlled adult asthma

“…We think that this can be explained as follows: Extracellular IL-26 protein in BAL samples reflects the production and release from several cellular sources, including structural cells such as bronchial epithelial cells and lung fibroblasts, as well as leukocytes. 4,8,9 In contrast, the IL-26 mRNA that we quantified to assess gene expression is likely to originate exclusively from luminal leukocytes in the airways.…”

<p>Sputum IL-26 Is Overexpressed in Severe Asthma and Induces Proinflammatory Cytokine Production and Th17 Cell Generation: A Case–Control Study of Women</p>

“…41 Viral stimulation of bronchial epithelial cells induces IL-26 production that is enhanced by IL-17, suggesting a role to IL-26 in asthma attacks. 18 In the same way, modifications of airways microbiota have been reported in severe asthma, together with a possible role of bacteria in the severity of asthma. 42,43 The role of macrophages, which are a prominent source of IL-26 during activation of anti-bacterial host defense, should be more deeply investigated.…”

“…Several resident and inflammatory pulmonary cells express and release IL-26. 14,18 A local production has been demonstrated by bronchial and lung biopsies with immunostaining of bronchial epithelial cells and macrophages/ monocytes. 35 Lung fibroblasts participate as well to IL26 production.…”

“…17 Human alveolar macrophages and bronchial epithelial cells are able to produce IL-26, acting then as a critical immune barrier. 18 Moreover, IL-26 enhances the chemotactic response of human neutrophils to bacterial and inflammatory stimuli. 12 In this way, Che et al 19 found increased extracellular IL-26 protein in the airways of long-term smokers in vivo.…”