Abstract
AbstractLipopolysaccharide (LPS) is an endotoxin that can cause an acute inflammatory response. Nitric oxide (NO) is one of the most important innate immune system components and is synthesized by inducible NOS (iNOS) in macrophages in response to stimulation with LPS. LPS activates the RAS-RAF-mitogen-activated protein kinase/ERK kinase (MEK)-extracellular-signal-regulated kinase (ERK) signaling cascade in macrophages. The purpose of this study was to examine how the combination of LPS and MEK inhibitors, which have been used as anticancer agents in recent years, affects inflammation. We showed that MEK inhibitors enhanced iNOS expression and NO production in LPS-stimulated mouse bone marrow-derived macrophages. A MEK inhibitor increased the mortality rate in mice with LPS-induced inflammation. The expression of the cytokine interleukin-12 (IL-12) in macrophages was enhanced by the MEK inhibitor, as shown by a cytokine array and ELISA. IL-12 enhanced iNOS expression and NO production in response to LPS. We also showed that tumor necrosis factor (TNF-α) was secreted by macrophage after stimulation with LPS and that TNF-α and IL-12 synergistically induced iNOS expression and NO production. An anti-IL-12 neutralizing antibody prevented NO production and mortality in an LPS-induced inflammation mouse model in the presence of a MEK inhibitor. These results suggest that the MEK inhibitor increases the mortality rate in mice with LPS-induced inflammation through IL-12-NO signaling.
Funder
MEXT | Japan Society for the Promotion of Science
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
Reference56 articles.
1. Kennedy LB, Salama AKS. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020;70:86–104.
2. Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020;17:807–21.
3. Felgner S, Kocijancic D, Frahm M, Weiss S. Bacteria in cancer therapy: renaissance of an old concept. Int J Microbiol. 2016;2016:8451728.
4. Mills H, Acquah R, Tang N, Cheung L, Klenk S, Glassen R, et al. The use of bacteria in cancer treatment: a review from the perspective of cellular microbiology. Emerg Med Int. 2022;2022:8127137.
5. Felgner S, Kocijancic D, Frahm M, Curtiss R 3rd, Erhardt M, Weiss S. Optimizing Salmonella enterica serovar Typhimurium for bacteria-mediated tumor therapy. Gut Microbes. 2016;7:171–7.