IL-13 regulates IL-17C expression by suppressing NF-?B-mediated transcriptional activation in airway epithelial cells.

Yamanaka K1, Fujisawa T2, Kusagaya H3, Mori K3, Niwa M3, Furuhashi K4, Kono M4, Hamada E1, Suda T3, Maekawa M1
Source: Biochem Biophys Res Commun
Publication Date: (2017)
Issue: 495: 1534-1540
Cells used in publication:
Epithelial, bronchial (NHBE), human
Species: human
Tissue Origin: lung


The cytokine interleukin (IL)-17C is highly expressed in epithelial tissues and involved in innate immune responses; however, the regulation of IL-17C expression in the airways remains poorly understood. Here, we show that IL-1ß strongly induces both IL-17C mRNA and protein expression in primary normal human bronchial epithelial cells. Conversely, IL-13 significantly reduced the IL-1ß-induced IL-17C expression. Attenuation of the nuclear factor (NF)-?B-signaling pathway using an NF-?B-subunit p65-specific small-interfering RNA (siRNA), reduced IL-1ß-induced IL-17C expression, demonstrating the importance of NF-?B signaling in IL-17C regulation. The inhibitory effects of IL-13 on IL-17C expression were abolished when the Janus kinase (JAK)/signal transducer and activator of transcription 6 (STAT6)-signaling pathway was impaired, using either the JAK inhibitor ruxolitinib or a STAT6-specific siRNA. Western blot analysis demonstrated that IL-1ß promoted both I?B-a phosphorylation and degradation, and p65 nuclear translocation. Although IL-13 induced STAT6 phosphorylation and nuclear translocation, it did not affect the activation of the IL-1ß-mediated NF-?B-pathway. Using chromatin immunoprecipitation, we confirmed that IL-1ß enhanced p65 binding to regions within the IL-17C promoter that flank putative NF-?B-binding sites (-130/-120 and -157/-147). Interestingly, IL-13 treatment reduced the IL-1ß-mediated p65 binding to these regions. These findings demonstrate that NF-?B-mediated transcriptional mechanisms are critically involved in the IL-1ß-mediated IL-17C induction, and that IL-13 negatively regulates this induction by suppressing NF-?B-based transcriptional activation