Proteasomal inhibition after injury prevents fibrosis by modulating TGF-β₁signalling

Abstract

Background The development of organ fibrosis after injury requires activation of transforming growth factor β1 which regulates the transcription of profibrotic genes. The systemic administration of a proteasomal inhibitor has been reported to prevent the development of fibrosis in the liver, kidney and bone marrow. It is hypothesised that proteasomal inhibition would prevent lung and skin fibrosis after injury by inhibiting TGF-β1-mediated transcription. Methods Bortezomib, a small molecule proteasome inhibitor in widespread clinical use, was administered to mice beginning 7 days after the intratracheal or intradermal administration of bleomycin and lung and skin fibrosis was measured after 21 or 40 days, respectively. To examine the mechanism of this protection, bortezomib was administered to primary normal lung fibroblasts and primary lung and skin fibroblasts obtained from patients with idiopathic pulmonary fibrosis and scleroderma, respectively. Results Bortezomib promoted normal repair and prevented lung and skin fibrosis when administered beginning 7 days after the initiation of bleomycin. In primary human lung fibroblasts from normal individuals and patients with idiopathic pulmonary fibrosis and in skin fibroblasts from a patient with scleroderma, bortezomib inhibited TGF-β1-mediated target gene expression by inhibiting transcription induced by activated Smads. An increase in the abundance and activity of the nuclear hormone receptor PPARγ, a repressor of Smad-mediated transcription, contributed to this response. Conclusions Proteasomal inhibition prevents lung and skin fibrosis after injury in part by increasing the abundance and activity of PPARγ. Proteasomal inhibition may offer a novel therapeutic alternative in patients with dysregulated tissue repair and fibrosis.

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

“…Of note, literature reports a reduction in the amount of TGF-β when the proteasome is directly inactivated by the specific inhibitor MG132 (Tashiro et al, 2003;Mutlu et al, 2012) and our data also confirmed this finding (Fig. S3A,E).…”

“…As expected (Tashiro et al, 2003;Mutlu et al, 2012), specific proteasome inhibition by MG132 induced a significant downregulation of TGF-β in high-glucose-treated cells (Fig. S3A,E).…”

“…Interestingly, there is also evidence that treatment with proteasome inhibitors prevents lung, skin and kidney fibrosis in different animal models (Tashiro et al, 2003;Luo et al, 2011;Mutlu et al, 2012). In fact, the ubiquitinproteasome system, in addition to its role in protein turnover, plays a modulation role in many cellular signaling pathways, including those involving TGF-β1 (Elliott et al, 2003;Mutlu et al, 2012). Remarkably, it has been described that c-Abl and Arg tyrosine kinases associate with and phosphorylate the proteasome PSMA7 subunit with consequent inhibition of proteasome activity (Liu et al, 2006).…”

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

“…To date, steroids are the most effective and utilized treatment, but new immune-modulatory drugs have been experimented to improve muscle repair by reducing inflammation and fibrosis of DMD animal models as anticytokines (anti-TNFα), 30 IL-6r blockade, 31 TGF-β blocker (suramin and pirfenidone) 32,33 and, more recently, Treg expansion. 13 Several evidences suggested that the proteasome is directly involved in the pathophysiology of organ fibrosis: inhibition of the proteasome could block TGF-β1 induced gene expression in primary human lung fibroblasts from healthy individuals and patients with IPF 34,35 and could reduce lung fibrosis in some animal models. 36,37 Indirectly, fibrosis is augmented by inflammatory pathogenesis that is also influenced by i-proteasome.…”

Hallmarks of the ageing lung

“…Concerning the degradative arms of the proteostasis network, impaired activation of autophagy has been suggested to contribute to IPF pathogenesis [235,236]. The role of proteasomal protein degradation in IPF development is unknown, but cannot be excluded as proteasome inhibitors have been shown to counteract bleomycin-induced fibrosis in mice [237].…”