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
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Research Support, N.I.H., Extramural
MeSH terms
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Allergens / immunology
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Animals
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Antigens, Surface / metabolism
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Asthma / genetics
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Asthma / immunology*
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Asthma / pathology
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Bronchi / chemistry
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Collagen / analysis
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ELAV Proteins
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ELAV-Like Protein 1
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Eosinophils / immunology*
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Heterogeneous Nuclear Ribonucleoprotein D0
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Heterogeneous-Nuclear Ribonucleoprotein D / metabolism
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Humans
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Mice
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Mice, Mutant Strains
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NIMA-Interacting Peptidylprolyl Isomerase
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Peptidylprolyl Isomerase / antagonists & inhibitors
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Peptidylprolyl Isomerase / genetics
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Peptidylprolyl Isomerase / metabolism*
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Protein Kinase C-alpha / metabolism
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Protein Phosphatase 2 / metabolism
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Pulmonary Fibrosis / genetics
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Pulmonary Fibrosis / immunology*
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Pulmonary Fibrosis / pathology
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RNA Stability
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RNA, Messenger / metabolism
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RNA-Binding Proteins / metabolism
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Rats
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Respiratory Hypersensitivity / genetics
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Respiratory Hypersensitivity / immunology*
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Respiratory Hypersensitivity / pathology
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism*
Substances
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Allergens
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Antigens, Surface
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ELAV Proteins
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ELAV-Like Protein 1
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ELAVL1 protein, human
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HNRNPD protein, human
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Heterogeneous Nuclear Ribonucleoprotein D0
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Heterogeneous-Nuclear Ribonucleoprotein D
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Hnrnpd protein, rat
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Hnrpd protein, mouse
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NIMA-Interacting Peptidylprolyl Isomerase
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RNA, Messenger
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RNA-Binding Proteins
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Transforming Growth Factor beta1
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Collagen
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Protein Kinase C-alpha
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Protein Phosphatase 2
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PIN1 protein, human
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Peptidylprolyl Isomerase
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Pin1 protein, mouse