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.
View: Text | PDF
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

×

Figure 6

Pin1 regulates TGF-β1 expression by in vivo activated Eos.

Options: View larger image (or click on image) Download as PowerPoint
Pin1 regulates TGF-β1 expression by in vivo activated Eos. (A) Viability...
(A) Viability of Eos after 3 day of culture. Purified Eos from BAL fluid (BAL Eos) were obtained from patients 2 days after segmental allergen challenge. Control peripheral blood Eos (PB Eos) were obtained from healthy donors. (B) RT-qPCR analysis for TGF-β1 mRNA. BAL Eos were left untreated (–) or incubated for 4 hours with juglone, 300 nM TAT-WW-Pin1, 300 nM TAT-GFP, 50 nM Gö6976, 5 nM okadaic acid, or 50 μM PD98059. (C) Cells left untreated or incubated for 24 hours with juglone before collection of culture medium and cells for ELISA and immunoblot. (D) Cells left untreated or treated for 10 minutes or 4 hours with juglone. Cytoplasmic lysates were immunoblotted. (E) Pin1 isomerase assay of cytoplasmic lysates from cells nontreated (NT) or treated for 4 hours with Gö6972 (5 nM), okadaic acid (5 nM), or juglone. Data in E are representative of 2 independent experiments. Error bars (A and B) indicate mean ± SD of 3 independent experiments with different donors. *P < 0.05 by Student’s t test in a 2-tailed analysis.