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- Title
Pin1 regulates TGF-beta1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis.
- Authors
Zhong-Jian Shen; Esnault, Stephane; Rosenthal, Louis A.; Szakaly, Renee J.; Sorkness, Ronald L.; Westmark, Pamela R.; Sandor, Matyas; Malter, James S.; Shen, Zhong-Jian
- 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.
- Subjects
EOSINOPHIL disorders; INFLAMMATION; ASTHMA; EXTRACELLULAR matrix proteins; MESSENGER RNA; CELLULAR immunity; NEUTRAL trade with belligerents; PATHOLOGY
- Publication
Journal of Clinical Investigation, 2008, Vol 118, Issue 2, p479
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI32789