Pin1 regulates TGF-β1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis
Zhong-Jian Shen, … , Matyas Sandor, James S. Malter
Zhong-Jian Shen, … , Matyas Sandor, James S. Malter
Published January 10, 2008
Citation Information: J Clin Invest. 2008;118(2):479-490. https://doi.org/10.1172/JCI32789.
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Research Article Immunology

Pin1 regulates TGF-β1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis

Abstract

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.

Authors

Zhong-Jian Shen, Stephane Esnault, Louis A. Rosenthal, Renee J. Szakaly, Ronald L. Sorkness, Pamela R. Westmark, Matyas Sandor, James S. Malter

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Figure 7

Pin1 blockade prevents peribronchiolar collagen deposition.

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Pin1 blockade prevents peribronchiolar collagen deposition. (A–C) Rats w...
(A–C) Rats were sensitized but challenged with vehicle (PBS) or subjected to allergen challenge without (RAG) or with juglone treatment (RAG+J) as described in Methods. (A) BAL fluid cells were collected, and the expression of TGF-β1 and collagen I mRNA was measured by qPCR. (B) Lung fibrosis was evaluated by trichrome staining and image analysis. Scale bar: 100 μm. (C) Lung collagen I and III mRNA expression was measured by qPCR. (D) Pin1-knockout and wild-type mice were sensitized but challenged with vehicle (PBS) or subjected to chronic allergen challenge with OVA as described in Methods. Lung fibrosis was evaluated by trichrome staining and image analysis. Scale bar: 100 μm. Error bars indicate mean ± SD of 3–6 animals per group. Data are representative of at least 2 independent experiments. *P < 0.05 by Student’s t test in a 2-tailed analysis.