Pro-inflammatory cytokine-driven PI3K/Akt/Sp1 signalling and H2S production facilitates the pathogenesis of severe acute pancreatitis

Severe acute pancreatitis (SAP) is a disease usually associated with systemic organ dysfunction or pancreatic necrosis. Most patients with SAP suffer from defective intestinal motility in the early phase of the disease. Additionally, SAP-induced inflammation produces hydrogen sulphide (H 2 S) that impairs the gastrointestinal (GI) system. However, the exact mechanism of H 2 S in the regulation of SAP is yet to be elucidated. In the present paper, we used a rat model of SAP to evaluate the role of H 2 S on intestinal motility by counting the number of bowel movements and investigating the effect of H 2 S on inflammation. We treated colonic muscle cells (CMCs) with SAP plasma, tumour necrosis factor-α (TNF-α) or interleukin-6 (IL-6) and measured the expressions of H 2 S-producing enzymes cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS) and Sp1 and PI3K/Akt by using quantitative PCR, Western blotting and immunohistochemical detection. We used the PI3K inhibitor LY294002 and the siRNA si- Sp1 to suppress the activity of the PI3K/Akt/ Sp1 signalling pathway. We found that, in the SAP rat model, H 2 S facilitated an inhibitory effect on intestinal motility and enhanced the inflammatory response caused by SAP ( P <0.05). The expressions of CSE and CBS in CMCs were significantly increased after treatment with TNF-α or IL-6 ( P <0.05). Blocking the PI3K/Akt/ Sp1 pathway remarkably inhibited the synthesis of CSE and CBS. Our data demonstrated that H 2 S plays a vital role in the pathogenesis of SAP and that SAP is modulated by inflammation driven by the PI3K/Akt/ Sp1 signalling pathway.