Abstract
Systemic fibrosing or sclerotic disorders are life-threatening, but only very limited treatment modalities are available for them. In recent years, periostin (POSTN), a major extracellular matrix component, was established by several studies as a novel key player in the progression of systemic fibrotic disease. In this research, we revealed the involvement of oxidative stress in the expression of POSTN induced by TGF-β1 and IL-13 in dermal fibroblasts. We found that the antioxidant cinnamaldehyde activated the NRF2/HMOX1 pathway. Cinnamaldehyde also alleviated TGF-β1- and IL-13-mediated production of reactive oxygen species and subsequent POSTN upregulation in dermal fibroblasts. In contrast, NRF2 silencing abolished the cinnamaldehyde-mediated downregulation of POSTN. These results suggest that cinnamaldehyde is a broad inhibitor of POSTN expression covering both TGF-β1 and IL-13 signaling. Cinnamaldehyde may thus be beneficial for the treatment of systemic fibrotic diseases.
Highlights
Periostin (POSTN) is a matricellular protein that is profoundly involved in the development and progression of fibrotic diseases as well as allergy and oncogenesis [1,2,3,4,5]
The mechanisms by which POSTN expression is regulated in fibrotic disease and their relationships with oxidative stress have remained elusive
We made the following key findings, which shed light on the mechanisms involved: (i) CIN activates nuclear factor erythroid-derived 2-like 2 (NRF2) signaling and upregulates HMOX1 production in dermal fibroblasts. (ii) CIN inhibits POSTN expression induced by transforming growth factor-β1 (TGF-β1) and IL-13 in dermal fibroblasts. (iii) Knockdown of NRF2 upregulates mRNA expression of constitutive and TGF-β1- and IL-13-induced POSTN. (iv) The CIN-mediated inhibition of POSTN expression induced by TGF-β1 and IL-13 is dependent on NRF2 signaling. (v) The same kind of regulation via NRF2 signaling controls other profibrotic molecules, namely, TNC, vascular endothelial growth factor (VEGF), and connective tissue growth factor (CTGF)
Summary
Periostin (POSTN) is a matricellular protein that is profoundly involved in the development and progression of fibrotic diseases as well as allergy and oncogenesis [1,2,3,4,5]. In Postn-deficient mice, bleomycin-induced fibrosis is canceled compared to wild-type control mice [4]. The expression of POSTN is upregulated in the lesional skin of scleroderma patients [4, 6, 7]. Serum POSTN levels are elevated in scleroderma as well as in pulmonary fibrosis [7, 8]. It has been shown that the downregulation of POSTN attenuates the profibrotic response of hepatic stellate cells [9]. Fibrosis is a characteristic feature in the pathogenesis of a wide spectrum of diseases, including systemic sclerosis, pulmonary fibrotic disorders, renal fibrotic disease, and liver cirrhosis. Antifibrotic treatments are currently limited [10,11,12,13,14,15,16,17,18], recent studies have demonstrated that the activation of nuclear factor erythroid-derived 2-like 2
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