Allergy and Asthma: Regulation of TGF 1 PINned down
Inhibiting the peptidyl–prolyl isomerase PIN1 in models of allergen-induced inflammation reduces allergic lung fibrosis, suggesting that PIN1 could be a therapeutic target for the treatment of chronic asthma.
Chronic asthma is characterized by eosinophilic inflammation, fibrosis, airway remodelling and collagen deposition. It is known that the production of transforming growth factor-1 (TGF1) by eosinophils drives airway remodelling and facilitates ongoing inflammation but it is not known how TGF1 production is regulated in these cells. Now, a study in The Journal of Clinical Investigation shows that the peptidyl-prolyl isomerase PIN1 (protein NIMA-interacting 1) regulates the production of TGF1 by human eosinophils, and that inhibition or ablation of PIN1 in mouse and rat models of chronic pulmonary inflammation reduces allergic lung fibrosis.
 |  |
PIN1 has previously been shown by this group to regulate the expression of granulocyte/macrophage colony-stimulating factor by eosinophils. So, using a specific PIN1 inhibitor, juglone (as well as dominant-negative PIN1 peptides) the authors examined TGF1 production by activated human eosinophils and found that Tgfb1 mRNA accumulation required PIN1 activity. Protein kinase C (PKC) and protein phosphatase 2A (PP2A) were shown to associate with and control the peptidyl-prolyl isomerase activity of PIN1. Further analysis showed that PIN1 associated with several AU-rich element (ARE)-binding proteins (AREBPs) that regulate Tgfb1 mRNA stability, and that activation of PIN1 by PKC and PP2A following eosinophil activation resulted in the release of destabilizing AREBPs from Tgfb1 mRNA. Inhibition of PIN1 resulted in increased Tgfb1 mRNA exosomal degradation in human activated eosinophils.
Using a rat model of allergen-induced inflammation, the authors showed that inhibition of PIN1 by juglone resulted in lower numbers of eosinophils in the bronchoalveolar lavage (BAL) fluid, reduced TGF1 and type I collagen expression by BAL cells and decreased lung fibrosis compared with controls. In addition, chronic allergen challenge of sensitized Pin1-/- mice resulted in reduced lung collagen deposition compared with wild-type mice.
So, the data indicate that PIN1 is an important regulator of Tgfb1 mRNA stability in eosinophils and that PIN1 could be a therapeutic target for the treatment of chronic asthma.
Olive Leavy
References
- Shen, Z.-J. et al. Pin1 regulates TGF-1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis. J. Clin. Invest. 118, 479–490 (2008) | Article | PubMed |
 more stories
| 
