Involvement of the p38 MAPK-NLRC4-Caspase-1 Pathway in Ionizing Radiation-Enhanced Macrophage IL-1β Production

• Published in: International journal of molecular sciences 2022-11, Vol.23 (22), p.13757
• Main Authors: Baik, Ji Sue, Seo, You Na, Lee, Young-Choon, Yi, Joo Mi, Rhee, Man Hee, Park, Moon-Taek, Kim, Sung Dae
• Format: Article
• Language: English
• Subjects: Apoptosis; c-Jun protein; Caspase 1 - metabolism; Caspase-1; Cell activation; Cell cycle; Colorectal carcinoma; Cytokines; Enzyme inhibitors; Enzymes; Extracellular signal-regulated kinase; Gene expression; IL-1β; Immune system; Inflammasomes; Inflammasomes - metabolism; Ionizing radiation; JNK protein; Kinases; Lipopolysaccharides; Lipopolysaccharides - metabolism; Lipopolysaccharides - pharmacology; macrophage; Macrophages; Macrophages - metabolism; Malignancy; MAP kinase; Mitogen-Activated Protein Kinase 14 - metabolism; NLRC4; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Protein expression; Protein kinase; Proteins; Radiation; Radiation, Ionizing; RNA-mediated interference; Transcription factors; Tumor microenvironment; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232213757

Macrophages are abundant immune cells in the tumor microenvironment and are crucial in regulating tumor malignancy. We previously reported that ionizing radiation (IR) increases the production of interleukin (IL)-1β in lipopolysaccharide (LPS)-treated macrophages, contributing to the malignancy of colorectal cancer cells; however, the mechanism remained unclear. Here, we show that IR increases the activity of cysteine-aspartate-specific protease 1 (caspase-1), which is regulated by the inflammasome, and cleaves premature IL-1β to mature IL-1β in RAW264.7 macrophages. Irradiated RAW264.7 cells showed increased expression of NLRC4 inflammasome, which controls the activity of caspase-1 and IL-1β production. Silencing of NLRC4 using RNA interference inhibited the IR-induced increase in IL-1β production. Activation of the inflammasome can be regulated by mitogen-activated protein kinase (MAPK)s in macrophages. In RAW264.7 cells, IR increased the phosphorylation of p38 MAPK but not extracellular signal-regulated kinase and c-Jun N-terminal kinase. Moreover, a selective inhibitor of p38 MAPK inhibited LPS-induced IL-1β production and NLRC4 inflammasome expression in irradiated RAW264.7 macrophages. Our results indicate that IR-induced activation of the p38 MAPK-NLRC4-caspase-1 activation pathway in macrophages increases IL-1β production in response to LPS.