Eosinophilic inflammation is a cornerstone of chronic asthma that often culminates in subepithelial fibrosis with variable airway obstruction. Pulmonary eosinophils (Eos) are a predominant source of TGF-β1, which drives fibroblast proliferation and extracellular matrix deposition. We investigated the regulation of TGF-β1 and show here that the peptidyl-prolyl isomerase (PPIase) Pin1 promoted the stability of TGF-β1 mRNA in human Eos. In addition, Pin1 regulated cytokine production by both in vitro and in vivo activated human Eos. We found that Pin1 interacted with both PKC-α and protein phosphatase 2A, which together control Pin1 isomerase activity. Pharmacologic blockade of Pin1 in a rat asthma model selectively reduced eosinophilic pulmonary inflammation, TGF-β1 and collagen expression, and airway remodeling. Furthermore, chronically challenged Pin1–/– mice showed reduced peribronchiolar collagen deposition compared with wild-type controls. These data suggest that pharmacologic suppression of Pin1 may be a novel therapeutic option to prevent airway fibrosis in individuals with chronic asthma.
Zhong-Jian Shen, Stephane Esnault, Louis A. Rosenthal, Renee J. Szakaly, Ronald L. Sorkness, Pamela R. Westmark, Matyas Sandor, James S. Malter
Title and authors | Publication | Year |
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The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation
M Nechama, J Kwon, S Wei, AT Kyi, RS Welner, IZ Ben-Dov, MS Arredouani, JM Asara, CH Chen, CY Tsai, KF Nelson, KS Kobayashi, E Israel, XZ Zhou, LK Nicholson, KP Lu |
Nature Communications | 2018 |
Prolyl isomerase Pin1: a promoter of cancer and a target for therapy
Y Chen, Y Wu, H Yang, X Li, M Jie, C Hu, Y Wu, S Yang, Y Yang |
Cell Death and Disease | 2018 |
PIN1 in Cell Cycle Control and Cancer
CW Cheng, E Tse |
Frontiers in pharmacology | 2018 |
TLR-7 Stress Signaling in Differentiating and Mature Eosinophils Is Mediated by the Prolyl Isomerase Pin1
ZJ Shen, J Hu, V Kashi, YA Bochkov, JE Gern, JS Malter |
Journal of immunology (Baltimore, Md. : 1950) | 2018 |