TRAF6-NF-κB Signaling Pathway Regulates the Expression of MMPs and Oxidative Stress Response in Mice with Biliary Pancreatitis
GULISITAN Abula, HU Jiali, HALINA, et al
Xinjiang Uygur Autonomous Region People's Hospital / Xinjiang Clinical Medical Research Center for Digestive System Diseases, Xinjiang Urumqi 830000, China
Abstract：Objective: To investigate the regulatory role of the tumor necrosis factor receptor-associated factor 6 (TRAF6)-nuclear factor κB (NF-κB) signaling pathway in mice with biliary pancreatitis, particularly its effects on the expression of matrix metalloproteinases (MMPs) and oxidative stress response. Methods: Twenty-four adult male C57BL/6J mice were randomly divided into three groups, with eight mice in each group: normal group (Group I), model group (Group II), and model + C25-140 group (Group III). C25-140 is a specific inhibitor of TRAF6 and NF-κB activity. The pancreatic organ-body ratio was measured in each group. Western blot was used to detect the expression of TRAF6, NF-κB p65, phosphorylated NF-κB p65 (p-NF-κB p65), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), MMP-2, and MMP-9 in pancreatic tissue. Additionally, levels of IL-1β, IL-6, TNF-α, α-amylase, and lipase in the serum were measured using enzyme-linked immunosorbent assay (ELISA) or kit methods. Results: Compared to Group I, Group II showed a significant increase in the pancreatic organ-body ratio (P<0.05), as well as significantly higher levels of IL-1β, IL-6, TNF-α, α-amylase, and lipase in both pancreatic tissue and serum (all P<0.05). Compared to Group II, these indicators were significantly lower in Group III (all P<0.05). TRAF6 and p-NF-κB p65 expressions were significantly upregulated in Group II compared to Group I (both P<0.05), while NF-κB p65 expression showed no significant difference (P>0.05). Group III showed significant downregulation of TRAF6 and p-NF-κB p65 compared to Group II (both P<0.05), with no significant difference in NF-κB p65 expression (P>0.05). MMP-2 and MMP-9 expressions in pancreatic tissue were significantly upregulated in Group II compared to Group I (both P<0.05). Group III showed significant downregulation of MMP-2 and MMP-9 compared to Group II (both P<0.05). Levels of reactive oxygen species (ROS) and malondialdehyde (MDA) were significantly increased, whereas superoxide dismutase (SOD) levels were significantly decreased in Group II compared to Group I (all P<0.05). In contrast, ROS and MDA levels were significantly decreased, and SOD levels were significantly increased in Group III compared to Group II (all P<0.05). Conclusion: The TRAF6-NF-κB signaling pathway plays an important regulatory role in the inflammatory response, MMP-2 and MMP-9 expression, and oxidative stress response in mice with biliary pancreatitis. The specific inhibitor C25-140 alleviates the inflammatory response, reduces MMPs expression, and mitigates oxidative stress response in these mice by inhibiting the TRAF6-NF-κB signaling pathway.
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