Phosphoinositide 3-kinase/protein kinase B regulates inflammation severity via signaling of Toll-like receptor 4 in severe acute pancreatitis

Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) has been indicated to serve an important role in the pathogenesis of inflammatory diseases. It was previously demonstrated that the PI3K/Akt inhibitor wortmannin alleviated the severity of inflammation and improved the survival rate in rats with induced severe acute pancreatitis (SAP), which indicates that PI3K/Akt may serve a role in the pathogenesis of acute pancreatitis. To date, the mechanism by which PI3K/Akt regulates inflammation has not been elucidated. In the present study, it was hypothesized that PI3K/Akt may be invovled in SAP inflammation via regulation of the Toll-like receptor 4 (TLR4) signaling pathway. Rats with SAP were treated with the PI3K/Akt agonist insulin-like growth factor (IGF)-1, which alleviated the severity of inflammation in a dose-dependent manner. Furthermore, to better understand the role of PI3K/Akt in inflammation, RAW264.7 murine macrophages were stimulated with IGF-1 and wortmannin alone or together before the induction of inflammation by treatment with lipopolysaccharide (LPS). The results indicated that LPS stimulated overexpression of TLR4, myeloid differentiation primary response gene 88 (MyD88), PI3K, Akt, p38MAPK and NF-Bp65 mRNA, and increased the levels of tumor necrosis factor (TNF)- and interleukin (IL)-6 in RAW264.7 cells compared with the control group. The levels of all detected factors were increased by stimulation with IGF-1, whereas these levels were decreased following treatment with wortmannin alone, and the effect of IGF-1 was abolished by wortmannin in RAW264.7 cells. In vivo studies indicated that IGF-1 produced the same anti-inflammatory effect as wortmannin and that expression of TLR4, p38MAPK and NF-Bp65 decreased following treatment with IGF-1. These findings indicate that PI3K/Akt may take part in the progression of SAP by regulating the TLR4 signaling pathway and that IGF-1 can inhibit inflammation in SAP rats.