Thioredoxin-interacting protein deficiency protects against severe acute pancreatitis by suppressing apoptosis signal-regulating kinase 1

by Selleckchem | Jul 28 2023

Acute pancreatitis is a common acute inflammatory abdominal disease. When acute pancreatitis progresses to severe acute pancreatitis (SAP), it can lead to systemic inflammation and even multiple organ failure. Thioredoxin-interacting protein (TXNIP) is an important protein involved in redox reactions of the inflammatory response. However, the specific role of TXNIP in SAP remains unclear. In this study, we investigated the role of thioredoxin interacting protein (TXNIP) in acute pancreatitis when induced by high doses of arginine. We found that pancreatic damage and the inflammatory response associated with acute pancreatitis were largely restrained in TXNIP knock-out mice but were enhanced in mice overexpressing TXNIP. Interestingly, the phosphorylation of p38, JNK, and ASK1 diminished in TXNIP-KO mice with pancreatitis in comparison with wild-type mice. The role of oxidative stress in SAP was explored in two models: TXNIP and AVV-TXNIP. TXNIP knockdown or the inhibition of ASK1 by gs-4997 abrogated the increase in p-p38, p-JNK, and p-ASK1 in AR42J cells incubated with L-Arg. The administration of gs-4997 to mice with pancreatitis largely reduced the upregulation of IL-6, IL-1β, TNF-α, and MCP-1. Systemic inflammatory reactions and injury in the lungs and kidneys were assessed in TXNIP-KO and AVV-TXNIP mice with expected outcomes. In conclusion, TXNIP is a novel mediator of SAP and exerts action by regulating inflammatory responses and oxidative stress via the ASK1-dependent activation of the JNK/p38 pathways. Thus, targeting TXNIP may represent a promising approach to protect against SAP.

Comments:

The provided text describes a study that investigated the role of thioredoxin-interacting protein (TXNIP) in acute pancreatitis, specifically induced by high doses of arginine. Here's a summary of the key findings and conclusions of the study:

1. TXNIP's role in acute pancreatitis: The study found that TXNIP plays a significant role in acute pancreatitis. When TXNIP was knocked out in mice, pancreatic damage and the associated inflammatory response were largely restrained. On the other hand, mice overexpressing TXNIP exhibited enhanced pancreatic damage and inflammation.

2. TXNIP and phosphorylation of signaling proteins: The study observed that the phosphorylation of p38, JNK, and ASK1 (signaling proteins involved in inflammation) was diminished in TXNIP knock-out mice with pancreatitis compared to wild-type mice. This suggests that TXNIP influences the activation of these signaling pathways in acute pancreatitis.

3. Role of oxidative stress: The study explored the role of oxidative stress in severe acute pancreatitis (SAP) using two models: TXNIP and AVV-TXNIP. TXNIP knockdown or the inhibition of ASK1 with gs-4997 prevented the increase in phosphorylated p38, JNK, and ASK1 in cells treated with L-Arginine. Additionally, administering gs-4997 to mice with pancreatitis reduced the upregulation of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, MCP-1).

4. Systemic effects: The study assessed systemic inflammatory reactions and injury in the lungs and kidneys of TXNIP knock-out and AVV-TXNIP mice. The results aligned with the expected outcomes, suggesting that TXNIP influences the systemic effects associated with severe acute pancreatitis.

5. Potential therapeutic target: Based on the findings, the study concludes that targeting TXNIP could be a promising approach to protect against severe acute pancreatitis. By regulating inflammatory responses and oxidative stress via the ASK1-dependent activation of the JNK/p38 pathways, inhibiting TXNIP could potentially alleviate pancreatic damage and systemic inflammation associated with SAP.

It's important to note that the information provided is a summary of a hypothetical study, and it's always essential to refer to the original research paper for complete and accurate details.