Pin1 Regulates TGF-beta1 Production by Activated Human and Murine Eosinophils and Contributes to Allergic Lung Fibrosis

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2008 Jan 12

PMID 18188456

Citations 57

Authors

Zhong-Jian Shen

Stephane Esnault

Louis A Rosenthal

Renee J Szakaly

Ronald L Sorkness

Pamela R Westmark

Matyas Sandor

James S Malter

Affiliations

Soon will be listed here.

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-beta1, which drives fibroblast proliferation and extracellular matrix deposition. We investigated the regulation of TGF-beta1 and show here that the peptidyl-prolyl isomerase (PPIase) Pin1 promoted the stability of TGF-beta1 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-alpha 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-beta1 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.

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