CISH is a negative regulator of IL-13-induced CCL26 production in lung fibroblasts

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  • Takeshima Hideyuki
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo
  • Horie Masafumi
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo Division for Health Service Promotion, The University of Tokyo Division of Pulmonary, Critical Care and Sleep Medicine and Hastings Center for Pulmonary Research, Department of Medicine, and Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California
  • Mikami Yu
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo Department of Clinical Laboratory Medicine, The University of Tokyo Hospital
  • Makita Kosuke
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo
  • Miyashita Naoya
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo
  • Matsuzaki Hirotaka
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo
  • Noguchi Satoshi
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo
  • Urushiyama Hirokazu
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo
  • Hiraishi Yoshihisa
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo
  • Mitani Akihisa
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo Division for Health Service Promotion, The University of Tokyo
  • Borok Zea
    Division of Pulmonary, Critical Care and Sleep Medicine and Hastings Center for Pulmonary Research, Department of Medicine, and Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California
  • Nagase Takahide
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo
  • Yamauchi Yasuhiro
    Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo

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Abstract

<p>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.</p><p>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.</p><p>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.</p><p>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.</p>

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