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 3

Pin1 associates with and is downstream of PP2A.

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Pin1 associates with and is downstream of PP2A. (A) Lysates from resting...
(A) Lysates from resting cells were immunoprecipitated as described above (Figure 2D) followed by immunoblotting (antibodies, right margin). (B) RT-qPCR for TGF-β1 mRNA. Cells were treated as in Figure 2G. (C) Pin1 isomerase assay. Cells were treated as in Figure 1E. OA, okadaic acid (1 nM). (D and E) Immunoblot of cell lysates. Cells were treated as in B and immunoblotted with the antibodies shown. (F) Pin1 isomerase assay. Cells were treated as in C and Figure 2F. (G) RT-qPCR analysis for TGF-β1 mRNA. Eos were treated as in F for 4 hours. (H) Eos were left untreated or treated for 4 hours with HA. Cell lysates were immunoprecipitated with anti-PP2A followed by immunoblot. Lysate, 10% of lysates before immunoprecipitation. The data in A and D–H represent 1 of 2 independent experiments. 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.