Isoforskolin inhibits LUBAC/GSDMD/IL-1β cascades in pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease which affects 3 million people worldwide. Our previous study confirmed that isoforskolin (ISOF) can improve the status of the mouse with pulmonary fibrosis (PF). This study aimed to explore the effect of ISOF on linear ubiquitin chain assembly complex (LUBAC) in the cell model of PF induced by transforming growth factor-β1 (TGF-β1). Methods: The fibrosis of mice lung fibroblasts (MLGs) were stimulated by TGF-β1 to establish a PF cell model. ISOF (0.5 and 1.0 µmol/L) was administrated as treatment drug in cell model, while pirfenidone (PFD; 10 µmol/L) and dexamethasone (DXM; 25 µmol/L) were administrated as control drug. In addition, HOIP inhibitor-8 (HOIPIN-8), the inhibitor of LUBAC, was also administrated. The PF model of mice was established by intratracheal instillation of bleomycin (BLM). Meanwhile, the expressions of LUBAC subunits [shank-associated RH domain interaction protein (SHARPIN), heme oxidation IRP2 ubiquitin ligase 1L (HOIL-1L), and HOIL-1L interacting protein (HOIP)], gasdermin D (GSDMD), and interleukin-1beta (IL-1β) were detected by western blot. Results: The expression of LUBAC was increased in the cell model, while attenuated with 24 h administration of ISOF 0.5 or 1.0 µmol/L (P