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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

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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 1

Pin1 is required for TGF-β1 mRNA expression.

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Pin1 is required for TGF-β1 mRNA expression.
(A, B, C, and E) Reverse tr...
(A, B, C, and E) Reverse transcription and qPCR (RT-qPCR) analysis for TGF-β1 mRNA. (A) Eos left untreated (resting [R]) or incubated for 4 hours with HA alone (100 μg/ml in all experiments) or with juglone (0.1 or 1.0 μM) prior to analysis. (B) Cells incubated for 4 hours with HA alone, with 60–300 nM TAT-WW-Pin1 (WW) or TAT-GFP (GFP) prior to analysis. (C) Cells left untreated or incubated for the indicated times with HA alone or with juglone (1.0 μM) (HA+J) or juglone alone (J) before collection and analysis at the times shown. (D) Intracellular levels of TGF-β1 protein were measured by immunoblotting of total cell lysates under reducing conditions and signal quantitated by densitometry and normalized to β-actin. (E) ELISA for TGF-β1 protein. Cells left untreated or incubated for 24 hours with HA alone or with juglone before collection of culture medium. The data are mean of 2 independent experiments. (F) Decay of TGF-β1 mRNA. Cells were treated for 2 hours with HA alone or with juglone, followed by the addition of 50 μg/ml of DRB (5,6-dichloro-1-β-d-ribofuranosylbenzimidazole) to block transcription. Cells were then collected at the times shown for analysis. Error bars indicate mean ± SD of 3 independent experiments with different donors. *P < 0.05 by Student’s t test in a 2-tailed analysis.

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