The Role of Sphingosine Kinase 1 in Patients With Severe Acute Pancreatitis

Abstract

To investigate the role of sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) signaling in inflammatory response in severe acute pancreatitis (SAP). SAP is an acute inflammatory process of the pancreas, which may lead to systemic inflammatory response syndrome and multiorgan dysfunction syndrome. SphK1 and its product S1P have been implicated in inflammatory response and various immune cell functions. However, the potential role for SphK1/S1P in inflammatory response in SAP is still unclear. Twenty-two patients with SAP were enrolled in this study. SphK1 expression on peripheral neutrophils, monocytes, and lymphocytes was evaluated by flow cytometry. SphK enzymatic activity in neutrophils and lymphocytes was measured using a radiometric assay. The expression of S1P1 and S1P3 mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The serum levels of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), and IL-6 were measured by ELISA. The expression of SphK1 and SphK activity were markedly increased in peripheral immune cells in the early stage of SAP and then reduced in the restoration stage in the patients. Moreover, we found that the level of S1P3 mRNA in peripheral neutrophils and lymphocytes of SAP patients was significantly elevated in the early stage as compared with the healthy volunteers, and it reduced in the restoration period. SphK1 expression on human peripheral neutrophils, monocytes, and CD4(+) T lymphocytes were positively correlated with the APACHE (Acute Physiological and Chronic Health Evaluation) II scores in patients with SAP. The levels of serum proinflammatory cytokines including TNF-α, IL-1β, and IL-6 showed similar shifts with intracellular SphK1 expression in SAP patients. The authors identified a link between the SphK1 expression on peripheral immune cells and the severity of SAP. Observations showed a possible immunomodulating role for SphK1/S1P signaling in inflammatory response in SAP, suggesting that regulation of SphK1/S1P pathway may represent novel targets in the treatment of SAP.