Galunisertib (LY2157299), a transforming growth factor-β receptor I kinase inhibitor, attenuates acute pancreatitis in rats

Abstract

Galunisertib (LY2157299), a selective ATP-mimetic inhibitor of TGF-β receptor I (TGF-βRI), is the only known TGF-β pathway inhibitor. In the present study, we investigated the effect of galunisertib on taurocholate (TAC)-induced acute pancreatitis (AP) in rats, and the role of TGF-β and NF-κB signaling pathways. AP was induced by infusion of TAC into the pancreatic duct of Sprague-Dawley male rats (n=30). The rats (220±50 g) were administered galunisertib intragastrically [75 mg·kg-1·day-1 for 2 days (0 and 24 h)]. Serum IL-1β, IL-6, TNF-α, amylase (AMY), lipase (LIP), and myeloperoxidase (MPO) levels were measured by ELISA. NF-κB activity was detected by electrophoretic mobility shift assay (EMSA); NF-κBp65 and TGF-β1 proteins, as well as TGF-βRI and p-Smad2/3 proteins, were detected by western blot assay. Cell apoptosis was detected by TUNEL assay. H&E staining was used to evaluate the histopathological alterations of the pancreas. Galunisertib treatment attenuated the severity of AP and decreased the pancreatic histological score. In addition, number of apoptotic cells were significantly increased in the galunisertib-treated group (16.38±2.26) than in the AP group (8.14±1.27) and sham-operated group (1.82±0.73; P<0.05 and P<0.01, respectively). Galunisertib decreased the expression levels of TGF-βRI and p-Smad2/3 and inhibited NF-κB activation and p65 translocation compared with the sham-operated group. Furthermore, serum IL-1β, IL-6, TNF-α, AMY and LIP levels and tissue MPO activity were significantly decreased in the galunisertib-treated group. Our data demonstrate that galunisertib attenuates the severity of TAC-induced experimental AP in rats by inducing apoptosis in the pancreas, inhibiting the activation of TGF-β signals and NF-κB as well as the secretion of pro-inflammatory cytokines.

Targeted delivery of galunisertib attenuates fibrogenesis in an integratedex vivorenal transplant and fibrosis model

“…However, galunisertib combined with TGFβ treatment reduced TNF-α expression. We observed significantly lower IL-6 levels after 6 h NMP on both mRNA and protein level, as also observed in a previous study (20), suggesting anti-inflammatory effects. Additionally, galunisertib did not compromise renal function and viability, or led to significant higher levels of urinary NAG (21).…”

LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

“…LY functions through targeting TGFBRI and some studies have shown that LY is also able to downregulate TGFBRI expression [ 33 , 34 ]. The effect of LY on TGFB1 and TGFBR1 expression was assessed in HGSOC cell lines.…”

The immune imbalance in the second hit of pancreatitis is independent of IL-17A

“…Galunisertib, a TGF-β receptor I kinase inhibitor, has demonstrated the critical, stimulatory effects of TGF-β in pancreatitis by limiting the extent of disease in animal models (36). In vivo TGF-β has been shown to stimulate Th17 cells formation via numerous pathways (37) and levels have been shown to be elevated in early pancreatitis (38), however levels in the second week of the disease are unknown.…”