title: Pin1 regulates TGF-beta1 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-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.
authors.affiliation: Waisman Center for Developmental Disabilities, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA.
authors.forename: Zhong-Jian
authors.initials: ZJ
authors.lastname: Shen
authors.forename: Stephane
authors.initials: S
authors.lastname: Esnault
authors.forename: Louis A
authors.initials: LA
authors.lastname: Rosenthal
authors.forename: Renee J
authors.initials: RJ
authors.lastname: Szakaly
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Sorkness
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Westmark
authors.forename: Matyas
authors.initials: M
authors.lastname: Sandor
authors.forename: James S
authors.initials: JS
authors.lastname: Malter
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001980:Bronchi / Q000737:chemistry; D003094:Collagen / Q000032:analysis; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004804:Eosinophils / Q000276:immunology*; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000485:Allergens; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C000630988:Hnrnpd protein, rat; C000630987:Hnrpd protein, mouse; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D053773:Transforming Growth Factor beta1; D003094:Collagen; D051571:Protein Kinase C-alpha; D054648:Protein Phosphatase 2; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse