Effects and mechanism of the etanercept on pancreatic encephalopathy

Pancreatic encephalopathy (PE) is a common fatal complication of acute pancreatitis (AP). Proinflammatory cytokines such as tumor necrosis factor (TNF)alpha and interleukin (IL)6 are generated during AP, and act synergistically to promote PE and multisystem failure. Caeruleininduced AP provides a convenient model to explore the role of proinflammatory cytokines in PE. The aim of the present study was to examine the effect of the TNFalpha inhibitor etanercept in PE models and elucidate the regulatory mechanisms. To model PE in vitro, rat hippocampal H197/IGFIR neuronal cells were treated with 10 nmol/ml caerulein alone or in combination with etanercept (1, 10 or 100 micromol/ml). To model PE in vivo, rats were injected with 50 microg/kg caerulein alone or combined with 10 mg/kg etanercept. At 6 h after administration, it was noted that etanercept downregulated expression of TNFalpha, IL1beta and IL6 by negatively regulating NFkappaB (a master regulator of cytokine expression) signaling, and prevented the accumulation of reactive oxygen species. Conversely, etanercept promoted the expression of the neurotrophic and antiinflammatory hypoxiainducible factor 1 alpha (HIF1alpha). In rat hippocampus, etanercept also reduced the levels of TNFalpha, IL1beta and IL6, upregulated HIF1alpha expression and inhibited the inflammatory response to reduce edema and neural necrosis. Together, these data suggested that etanercept could attenuate caeruleininduced PE, at least in part via suppression of NFkappaB signaling and alleviation of oxidative stress.