IL-37 inhibited inflammation to improve gestational diabetes mellitus through the GSK3/NF-κB pathway.

PURPOSE: To investigate the role of IL-37 in gestational diabetes mellitus (GDM) and its potential mechanisms. METHODS: A GDM mouse model was constructed with a high-fat diet (HFD). The effects of IL-37 on glucose metabolism, insulin sensitivity, insulin resistance, and placental inflammation were examined using glucose and insulin tolerance tests, ELISA, western blot, HE staining, immunohistochemistry, immunofluorescence, and RT-qPCR. To further investigate the regulatory role of IL-37 in the GSK3/NF-κB pathway, experiments were repeated with the inclusion of DIF-3, a well-known activator of GSK3. RESULTS: The results indicated that the expression of IL-37 was decreased in mice with GDM. IL-37 overexpression could reduce placental inflammation, promote M2 polarization in macrophages, and decrease the mRNA levels of inflammation factors. In addition, the overexpression of IL-37 may improve abnormal glucose metabolism, enhance insulin sensitivity, and alleviate insulin resistance. Mechanistic studies have demonstrated that the anti-inflammatory and pro-glucose metabolism effects of IL-37 in GDM were reversed by the GSK activator DIF-3. After treatment with DIF-3, mice in the IL-37-treated group exhibited increased expression of GSK3 and p-NF-κB protein, along with decreased expression of IRS-1, p-Akt, and GLUT4 protein. These results consistently indicated that IL-37 may suppress inflammation to ameliorate GDM through the modulation of the GSK3/NF-κB pathway. CONCLUSION: IL-37 alleviated GDM by downregulating the activity of GSK-3/NF-κB. This modulation subsequently reduced inflammatory markers and improved insulin resistance. TRIAL REGISTRATION: Not applicable.