IL-10 alleviates ulcerative colitis by regulating mitochondrial function through reducing ISG15 expression

Background: Interleukin-10 (IL-10), an anti-inflammatory cytokine, has shown therapeutic effect on autoimmune diseases, yet its effects on UC remain unclear. This study aims to investigate whether the administration of IL-10 can suppress disease flares in ulcerative colitis (UC).

Methods: A UC model was established in mice using dextran sulfate sodium (DSS) to evaluate the therapeutic effect of IL-10. LPS-stimulated Caco-2 cells were utilized to explore the underlying molecular mechanisms, focusing on Apoptosis, inflammation, and oxidative stress.

Results: IL-10 administration significantly alleviated clinical symptoms in DSS-induced colitis, including promoting body weight recovery, increasing colon length, and reducing disease activity index scores. IL-10 repaired the intestinal mucosal barrier by inhibiting Apoptosis of intestinal epithelial cells, downregulating pro-inflammatory cytokines (IL-6, Interferon-γ, and IL-1β), and modulating oxidative stress markers, such as malondialdehyde (MDA) and superoxide dismutase (SOD). In LPS-stimulated Caco-2 cells, IL-10 protected against Apoptosis, oxidative stress, and inflammation. Bioinformatics analysis of control and IL-10 knockout mice showed a significant upregulation of Interferon-Stimulated Gene 15 (ISG15) after IL-10 knockout. In contrast, ISG15 expression was downregulated in the LPS + IL-10 group but upregulated in LPS-stimulated Caco-2 cells. These results suggest that ISG15 is a target gene of IL-10 and plays a role in Autophagy regulation. Furthermore, IL-10 enhanced Autophagy by increasing the protein expression of Atg7, and the LC3-II/LC3-I ratio, thereby reducing Apoptosis and oxidative stress in Caco-2 cells. Autophagy inhibition with 3-Methyladenine or overexpression of ISG15 diminished IL-10's protective effects.

Conclusion: This study demonstrates that IL-10 administration inhibits the progression of UC by activating Autophagy and modulating ISG15 expression. In the future, targeted delivery of IL-10 to the intestinal lamina propria may enhance therapeutic efficacy while minimizing systemic side effects.

Autophagy; IL-10; ISG15; Intestinal barrier; Mitochondrial function; Ulcerative colitis.