Pin1 regulates TGF-β1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis
Zhong-Jian Shen, Stephane Esnault, Louis A. Rosenthal, Renee J. Szakaly, Ronald L. Sorkness, Pamela R. Westmark, Matyas Sandor, James S. Malter
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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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 2

Pin1 associates with and is downstream of PKC-α.

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Pin1 associates with and is downstream of PKC-α. (A and C) RT-qPCR analy...
(A and C) RT-qPCR analysis for TGF-β1 mRNA. (A) Eos were treated as in Figure 1A. Gö, Gö6976; SA, safingol; PD, PD98059 (50 μM). (B) ELISA for TGF-β1 protein. Cells were treated as in Figure 1D. (C) Eos were treated as in A. HETE, 12(S)-HETE (10 nM/ml); TXA, thymeleatoxin (10 nM). (D) Eos were treated for 4 hours with HA alone or with juglone. Lysates were immunoprecipitated with anti-Pin1 followed by immunoblotting (as shown on right). Input, 10% of lysates before IP. The blot represents 1 of 2 independent experiments. (E and F) Pin1 isomerase assay of cytoplasmic lysates from untreated Eos (R) or Eos treated for 10 minutes with HA alone, with juglone, or with Gö6976 (HA+Gö) (E) or with 12(S)-HETE alone or with Gö6976 (HETE+Gö) (F). The kinetics (left) is representative of 3 independent experiments. The released Δ[pNA]/g of protein was calculated (right), as described (20). (G) Immunoblot of cell lysates from Eos treated for 4 hours with HA alone or with juglone or with 50 μM of MG132 (HA+J+MG). The blot represents 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.