Abstract
BackgroundImpairment of the blood-brain barrier (BBB) in severe acute pancreatitis (SAP) could result in life-threatening pancreatic encephalopathy. Interleukin-10 (IL-10) is a classical cytokine that is well-known for its strong immunoregulatory and anti-inflammatory abilities. However, whether and how IL-10 protects the BBB in SAP are still unclear.MethodsThis study includes in vivo experiments using a SAP rat model and in vitro experiments using an in vitro BBB model consisting of a monolayer of brain microvascular endothelial cells (BMECs). The study groups are divided into the control, SAP (in vivo)/TNF-α (in vitro), IL-10 treatment, IL-10 + signal transducer and activator of transcription 3 (STAT3) inhibitor S3I-201 treatment groups. Pancreatic pathological scores, serum amylase, serum TNF-α levels and BBB permeability by Evan’s blue assay in SAP rat models were evaluated. BMEC apoptosis in SAP rats or induced by TNF-αin vitro was detected by terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) and flow cytometry, separately. Expression levels of claudin-5 and proteins involved in the STAT3 signaling pathway were measured by Western blotting. Location and changes of junctional structure of claudin-5 on BMECs were assessed by immunohistochemistry and immunofluorescence.ResultsIn vivo, IL-10 alleviated the severity of inflammation, attenuated the increased BBB permeability in SAP rat models by reducing BMEC apoptosis via the STAT3 pathway and ameliorated the down-regulation of claudin-5 expression in BMECs; in vitro, IL-10 improved BBB integrity against TNF-α by attenuating BMEC apoptosis via the STAT3 pathway, the impairment of tight junction structure and the down-regulation of claudin-5 expression in BMECs.ConclusionsIL-10 improves BBB properties in SAP by attenuating the down-regulation of claudin-5 expression and the impairment of tight junctions and by STAT3 pathway-mediated anti-apoptotic effects on BMECs.
Highlights
Impairment of the blood-brain barrier (BBB) in severe acute pancreatitis (SAP) could result in lifethreatening pancreatic encephalopathy
We found that IL-10 induced anti-apoptotic effects via the signal transducer and activator of transcription 3 (STAT3) pathway by decreasing Bcl-2-associated X (Bax) expression while increasing B-cell lymphoma 2 (Bcl-2) expression in brain microvascular endothelial cells (BMECs)
In vivo experiments IL-10 alleviated the severity of inflammation and the increased BBB permeability in SAP rats All rats successfully underwent SAP model establishment, and saponification spots were observed on the mesentery and omentum when the rats were sacrificed
Summary
Impairment of the blood-brain barrier (BBB) in severe acute pancreatitis (SAP) could result in lifethreatening pancreatic encephalopathy. Interleukin-10 (IL-10) is a classical cytokine that is well-known for its strong immunoregulatory and anti-inflammatory abilities. Pancreatic encephalopathy is a serious complication in SAP and is associated with a mortality rate of 67% [2]. Though the pathogenesis is unclear, a close relationship between pancreatic encephalopathy and impairment of the blood-brain barrier (BBB) is commonly accepted. BMECs and peri-cellular tight junctions are basic and functional characteristics of the BBB. Severe inflammation has been shown to induce BMEC apoptosis, and impairment of peri-cellular tight junctions result in BBB dysfunction [5]. Attenuating BMEC apoptosis and the deterioration of tight junctions is beneficial for stabilizing the BBB.
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