Pin1 regulates TGF-beta1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis

J Clin Invest. 2008 Feb;118(2):479-90. doi: 10.1172/JCI32789.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allergens / immunology
  • Animals
  • Antigens, Surface / metabolism
  • Asthma / genetics
  • Asthma / immunology*
  • Asthma / pathology
  • Bronchi / chemistry
  • Collagen / analysis
  • ELAV Proteins
  • ELAV-Like Protein 1
  • Eosinophils / immunology*
  • Heterogeneous Nuclear Ribonucleoprotein D0
  • Heterogeneous-Nuclear Ribonucleoprotein D / metabolism
  • Humans
  • Mice
  • Mice, Mutant Strains
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / antagonists & inhibitors
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism*
  • Protein Kinase C-alpha / metabolism
  • Protein Phosphatase 2 / metabolism
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / immunology*
  • Pulmonary Fibrosis / pathology
  • RNA Stability
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism
  • Rats
  • Respiratory Hypersensitivity / genetics
  • Respiratory Hypersensitivity / immunology*
  • Respiratory Hypersensitivity / pathology
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • Allergens
  • Antigens, Surface
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • HNRNPD protein, human
  • Heterogeneous Nuclear Ribonucleoprotein D0
  • Heterogeneous-Nuclear Ribonucleoprotein D
  • Hnrnpd protein, rat
  • Hnrpd protein, mouse
  • NIMA-Interacting Peptidylprolyl Isomerase
  • RNA, Messenger
  • RNA-Binding Proteins
  • Transforming Growth Factor beta1
  • Collagen
  • Protein Kinase C-alpha
  • Protein Phosphatase 2
  • PIN1 protein, human
  • Peptidylprolyl Isomerase
  • Pin1 protein, mouse