IL-33/ST2 axis delays disc degeneration through PI3K/AKT-dependent regulation of nucleus pulposus cell proliferation and apoptosis

  • Cell Signal. 2026 Aug:144:112548. doi: 10.1016/j.cellsig.2026.112548.
Haoran Wang  1 ,  Ping Zhou  2 ,  Yanrui Chen  3 ,  Yi Li  4 ,  Jun Liu  5
Affiliations
  • 1. Department of Orthopaedics, Tongji Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200065, China. Electronic address: [email protected].
  • 2. Lab Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 3. Department of Orthopaedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 4. Department of Orthopaedics, Tongji Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200065, China.
  • 5. Department of Orthopaedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
PMID: 42025895 DOI: 10.1016/j.cellsig.2026.112548
Abstract

Objective: To investigate the proliferation and Apoptosis of nucleus pulposus cells stimulated by IL-33, as well as the activation of the PI3K/Akt signaling pathway in these cells, and to determine whether this pathway is regulated by the IL-33/ST2 axis.

Methods: Wild-type mice, IL-33 knockout (KO) mice, and ST2 KO mice were used to establish a model of intervertebral disc degeneration in the tail vertebrae. HE staining and Masson staining were employed to assess the degree of disc degeneration in the modeled regions. Immunofluorescence was conducted to verify the localization of IL-33 and Collagen-II, while ELISA was used to measure the expression levels of Collagen-II in the modeled areas. An in vitro model of nucleus pulposus cells was established, with IL-33 administered in a time and concentration gradient. Western blotting was used to detect changes in the expression of Collagen-II, Aggrecan, P-PI3K, and P-AKT. Additionally, flow cytometry was utilized to assess the cell cycle and Apoptosis of the nucleus pulposus cells in each group, and CCK-8 assays were performed to evaluate the proliferation of cells in each group.

Result: In the intervertebral disc degeneration group, the expression of IL-33 in the modeling area of mice was found to be downregulated. Furthermore, the degree of intervertebral disc degeneration in IL-33 and ST2 knockout mice was exacerbated compared to wild-type mice. With the extension of IL-33 stimulation time and the intensification of the effect, the proliferation activity of nucleus pulposus cells increased, while the degree of Apoptosis decreased. Additionally, IL-33 was able to activate the PI3K/Akt signaling pathway in nucleus pulposus cells, and this biological activity could be inhibited by Anti-ST2.

Conclusion: In conclusion, IL-33 can activate the PI3K/Akt signaling pathway in nucleus pulposus cells, promoting their proliferation and inhibiting Apoptosis, and this biological activity is regulated by the IL-33/ST2 axis.

Keywords
IL-33/ST2; Intervertebral disc degeneration; Nucleus pulposus cells; PI3K/AKT.
Products