Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 495, Issue 1, Pages 1534-1540Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2017.11.207
Keywords
IL-17C; NF-kappa B; Transcriptional mechanism; IL-13; IL-1 beta
Categories
Funding
- Japanese Society of Laboratory Medicine Fund for the Promotion of Scientific Research
- JSPS KAKENHI [15H04760]
- Grants-in-Aid for Scientific Research [15K09214, 15H04760] Funding Source: KAKEN
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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-1 beta strongly induces both IL-17C mRNA and protein expression in primary normal human bronchial epithelial cells. Conversely, IL-13 significantly reduced the IL-1 beta-induced IL-17C expression. Attenuation of the nuclear factor (NF)-kappa B-signaling pathway using an NF-kappa B-subunit p65-specific small interfering RNA (siRNA), reduced IL-1 beta-induced IL-17C expression, demonstrating the importance of NF-kappa 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-1 beta promoted both I kappa B-alpha 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-1 beta-mediated NF-kappa B-pathway. Using chromatin immunoprecipitation, we confirmed that IL-1 beta enhanced p65 binding to regions within the IL-17C promoter that flank putative NF-kappa B-binding sites (-130/-120 and 157/-147). Interestingly, IL-13 treatment reduced the IL-1 beta-mediated p65 binding to these regions. These findings demonstrate that NF-kappa B-mediated transcriptional mechanisms are critically involved in the IL-1 beta-mediated IL-17C induction, and that IL-13 negatively regulates this induction by suppressing NF-kappa B-based transcriptional activation. (C) 2017 Elsevier Inc. All rights reserved.
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