Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma

Abstract

Periostin is considered to be a matricellular protein with expression typically confined to cells of mesenchymal origin. Here, by using in situ hybridization, we show that periostin is specifically up-regulated in bronchial epithelial cells of asthmatic subjects, and in vitro, we show that periostin protein is basally secreted by airway epithelial cells in response to IL-13 to influence epithelial cell function, epithelial-mesenchymal interactions, and extracellular matrix organization. In primary human bronchial epithelial cells stimulated with periostin and epithelial cells overexpressing periostin, we reveal a function for periostin in stimulating the TGF-β signaling pathway in a mechanism involving matrix metalloproteinases 2 and 9. Furthermore, conditioned medium from the epithelial cells overexpressing periostin caused TGF-β-dependent secretion of type 1 collagen by airway fibroblasts. In addition, mixing recombinant periostin with type 1 collagen in solution caused a dramatic increase in the elastic modulus of the collagen gel, indicating that periostin alters collagen fibrillogenesis or cross-linking and leads to stiffening of the matrix. Epithelial cell-derived periostin in asthma has roles in TGF-β activation and collagen gel elasticity in asthma.airway fibrosis | fibroblasts | epithelial to mesenchymal transition | MMP-2 | MMP-9

Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

“…These results are consistent with the hypothesis that TGF-β secretion and its enhanced activity contribute to the demise of skeletal muscle in MD (9). However, one interesting possibility is that periostin functions as a key downstream effector of TGF-β that promotes its deleterious effects in MD (31). Indeed, in the absence of periostin, TGF-β appears to have a protective effect in MD disease progression by enhancing regeneration or by blunting other negative effects of this cytokine (14).…”

“…These findings support a complex interaction between periostin and TGF-β that may be related to the TGF-β paradox, where it can be both beneficial and deleterious depending on dosage and costimulatory factors (17). Periostin expression in epithelial cells has been shown to stimulate TGF-β signaling and lead to enhanced collagen production and expression of matrix metalloproteinase 2 and MMP9 for further matrix remodeling (31). Thus, periostin may indirectly alter TGF-β-dependent disease signaling by changing the composition of the ECM with respect to other known TGF-β-binding proteins that reside there, such as the latent TGF-β-binding proteins, fibrillins, and thrombospondin-1, as well as by effecting interactions with select integrins that alter the function of latency-associated peptides in controlling how TGF-β is activated and presented to receptors on surrounding cells (32).…”

Subtypes of Asthma Defined by Epithelial Cell Expression of Messenger RNA and MicroRNA

“…On the basis of these data, and the observation that periostin is secreted by airway epithelial cells (30), blood levels of periostin have been studied as a surrogate marker for airway eosinophilia (31) and as a method for predicting response to pharmacologic IL-13 blockade with lebrikizumab, and anti-IL-13 antibody (32).…”

The Role of Cytokines in the Pathogenesis of Bronchial Asthma and the Possibilities of Anti-Cytokine Therapy

“…A single dose of benralizumab reduced the number of serum eosinophils, and reduced the number of exacerbations. Lebrikizumab is a humanized monoclonal antibody that blocks IL-13, which induces periostin secretion by bronchial epithelial cells [33], stimulates IgE synthesis, bronchial fibrosis, and respiratory hypersensitivity [34]. J Corren et al [35] used lebrikizumab to treat 219 patients with BA.…”