Tumor-derived cyclooxygenase-2 fuels hypothalamic inflammation

• DOI: 10.1016/j.bbi.2024.11.002
• Publication Date: 2024-11-04T22:48:09Z
• Authors: Xiaolin Li; Xinxia Zhu; Parham Diba; Xuan Shi; Frank Vrieling; Fleur A.C. Jansen; Michiel G.J. Balvers; Ian de Bus; Peter R. Levasseur; Ariana Sattler; Paige C. Arneson-...; Mieke Poland; Renger F. Witkamp; Klaske van Norren; Daniel L. Marks
• Keywords: 0301 basic medicine; 0303 health sciences; Life Science

Hypothalamic inflammation often coincides with cancer and cachexia-anorexia. Prior work established the significance of tumor-derived inflammatory factors in triggering hypothalamic inflammation, yet precise mechanisms remained elusive. Here, we demonstrate that prostaglandin E2 (PGE2), produced tumor via cyclooxygenase-2 (COX-2), plays a pivotal role this context. PGE2 itself directly exerts pro-inflammatory effects on hypothalamus through EP4 receptor, while also augmenting NF-κB pathways presence host gut-derived pathogen-associated molecular patterns (PAMPs). In tumor-bearing mice, confirm synergistic interaction between COX-2/PGE2 host-derived lipopolysaccharide (LPS) amplifying inflammation. Supporting mechanism find tumor-specific knockout COX-2 attenuates improves survival mice. Together, these findings highlight tumor-associated fuelling They emphasize potential inhibition targeting gut permeability as novel therapeutic strategy for improving clinical outcomes patients.