1. CISH is a negative regulator of IL-13-induced CCL26 production in lung fibroblasts.
- Author
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Takeshima H, Horie M, Mikami Y, Makita K, Miyashita N, Matsuzaki H, Noguchi S, Urushiyama H, Hiraishi Y, Mitani A, Borok Z, Nagase T, and Yamauchi Y
- Subjects
- Cells, Cultured, Chemokine CCL26 genetics, Eosinophilia metabolism, Humans, Lung, STAT6 Transcription Factor genetics, STAT6 Transcription Factor metabolism, Signal Transduction, Suppressor of Cytokine Signaling Proteins genetics, Chemokine CCL26 metabolism, Fibroblasts metabolism, Interleukin-13 metabolism, Suppressor of Cytokine Signaling Proteins metabolism
- Abstract
Background: Bronchial asthma is a chronic airway disease characterized by eosinophilic airway inflammation. Lung fibroblasts activated by IL-13 serve as important sources of chemokines, such as eotaxins, contributing to persistent eosinophilic inflammation. Src-homology 2-containing protein (CISH), belonging to the suppressor of cytokine signaling (SOCS) family, acts as a negative regulator of cytokine induction. The aim of this study was to elucidate the role of CISH in the production of eosinophil chemotactic chemokines in human lung fibroblasts., Methods: Normal human lung fibroblasts were stimulated by IL-13, and global gene expression profile was assessed by cDNA microarray. Expression changes and downstream of IL-13 signaling were evaluated by quantitative RT-PCR, ELISA or western blotting. Loss- and gain-of-function analyses of CISH were performed by small interfering RNA and vector overexpression, respectively., Results: Ingenuity pathway analysis revealed that IL-13 induced chemokine signaling, including the eotaxin family, while significantly suppressing IFN-α/β signaling. Among eight SOCS family members, CISH was most strongly induced by IL-13 via phosphorylation of signal transducer and activator of transcription 6 (STAT6). Loss- and gain-of-function studies demonstrated that CISH negatively regulated the expression of CCL26., Conclusions: These findings suggest that CISH plays a key role in the eosinophilic inflammation associated with bronchial asthma by regulating IL-13-induced CCL26 production. Augmentation of CISH function could be a novel approach for treating eosinophilic inflammation in severe asthma., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)
- Published
- 2019
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