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.
Highlights
Interleukin (IL)-26 is a member of the IL-10 cytokine family that may be coproduced with archetype T-helper (Th) 17 cytokines including IL-17A and IL-22 [1,2,3]
The primary bronchial epithelial cells were exposed (24 h) to viral stimulation and we found that these cells contain the IL26 mRNA that was increased approximately 3 fold after stimulation with polycytidylic acid (poly-IC) (1μg/mL) (Figure 1A)
We found that increasing concentrations of poly-IC caused a corresponding increase in IL-26 protein release in the cell-free conditioned media (Figure 1B)
Summary
Interleukin (IL)-26 is a member of the IL-10 cytokine family that may be coproduced with archetype T-helper (Th) 17 cytokines including IL-17A and IL-22 [1,2,3]. IL-26 was discovered more than a decade ago [4], surprisingly few studies have addressed its involvement in human immunology and pathology. The synovial cell production of IL-26 induces bone mineralization in joint tissue from patients with the chronic inflammatory disease spondyloarthritis [8]. In a recent in vivo study [9], we forwarded evidence that endogenous IL-26 is abundant and involved in the local immune response against a bacterial stimulus, a toll-like receptor (TLR) 4 agonist, in healthy human airways. We demonstrated that IL-26 enhances the chemotactic response of neutrophils toward a bacterial stimulus and toward IL-8, while at the same time inhibiting the chemokinesis in these innate effector cells [9,10,11].
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