The Regulatory Mechanisms Of Interleukin-17Inhibiting GSK3β-mediated Activation Of Autophagy And The Therapeutic Application In Pulmonary Fibrosis

Pulmonary inflammation and pulmonary fibrosis are the common pathological features of interstitial lung diseases that result from a variety of reasons. Despite the pathogenesis of fibrosis remaining as an enigma, the polarization direction of adaptive immunity, especially the Thl and Th2responses, are critical for both resolution and development of pulmonary fibrosis. In addition, Thl7immune response is also involved in the regulation of pulmonary fibrosis.We recently find that IL-17A participates in the development of acute and chronic pulmonary fibrosis, and the blockade of IL-17A activity can attenuate bleomycin-or silica-induced pulmonary fibrosis by promoting the resolution of inflammation and the activation of autophagy. Autophagy is a cellular metabolic processes, mainly refers to the lysosomal degradation of the cell structure (such as organelles, nucleic acids or proteins and other biological macromolecules) to provide raw materials for the reconstruction of the cell regeneration and repair, and cell recycling. Although the induction of autophagy stimulating the collagen degradation in the fibrotic lung have been identified as a mechanism responsible for the anti-fibrotic role of targeting IL-17A, it remains to be clarified how IL-17A signaling pathway contribute to the autophagic regulation. In this study, we first provided the evidence that the phosphorylation of Bcl-2at residue serine70was reduced in the presence of IL-17A, and this reduction suppressed the ubiquitination degradation of Bcl-2, which subsequently attenuated autophagy by promoting the integration of Bcl-2and Beclin-1. Furthermore, we found that IL-17A-activated PI3K-glycogen synthase kinase-3β (GSK3β) signaling cascade was involved in the regulation of Bcl-2phosphorylation. Indeed, in response to IL-17A stimulation, PI3K (class I) was activated to phosphorylate the GSK3β at Ser9, which subsequently attenuated the interaction of GSK3β with Bcl-2. Interrupting the GSK3β and Bcl-2interaction precluded the phosphorylation of Bcl-2at Ser70which can trigger the ubiquitination degradation, and finally restrain the ubiquitination degradation of Bcl-2. Consequently, the decrease in the degradation of Bcl-2attenuated autophagy and promoted development of pulmonary fibrosis in mouse. These findings indicate that the IL-17A-PI3K-GSK3β-Bcl2signaling axis participates in the regulation of autophagy, which is attributed to be primarily responsible for the mechanism of IL-17A-induced pulmonary fibrosis.Autophagy, a self-catabolic process that maintains intracellular homeostasis, has been recently found to degrade the collagen in the process of tissue fibrosis. In this study, we report that SB216763, a potent and selective glycogen synthase kinase-3β inhibitor, significantly decreases the bleomycin-induced animal death and aggravated pulmonary inflammation, fibrosis, and lung function through stimulating the activity of autophagy. Indeed, we found that SB216763increases the expression of autophagy related protein and decreases the intergration of Bcl-2and Beclin-1. Further more, we found that SB216763up-regulates the binding of Bcl-2and GSK3β, which reduces the intergration of Bcl-2and Beclin-1. Our studies suggest that using a growth-regulating stimulator of autophagic activity, such as GSK3β inhibitor, may be a promising therapeutic strategy for the treatment of devastating fibroproliferative diseases such as idiopathic pulmonary fibrosis.