Effect of the NF-κB pathway agonist IL-1β in lung cancer cells

Liu, Dong (2021): Effect of the NF-κB pathway agonist IL-1β in lung cancer cells. Dissertation, LMU München: Medizinische Fakultät

Abstract

The inflammatory factors present in tumour microenvironments are essential for each step of tumour formation and development. Interleukin-1β (IL-1β) has strong pro-inflammatory activity, which is closely related to the malignant transformation of cells, tumour formation and metastasis. Canakinumab is an IL-1β inhibitory antibody. Recently, a large trial of canakinumab in cardiac patients indicated lower lung cancer incidence in patients treated with canakinumab compared to the controls. This finding is the basis for ongoing clinical trials of canakinumab in lung cancer. The activation of the nuclear factor κB (NF-κB) signalling pathway is often accompanied by inflammation or tumour growth. As well as participating in cell-cycle regulation, autophagy, aging, apoptosis, inflammatory responses, immune responses and other pathophysiological processes, NF-κB plays an important role in the occurrence, development, infiltration, metastasis and treatment of tumours. This work aimed to investigate the interactions between lung cancer cells (H838, H1339, H1650 and H1975) and immunocytes (macrophages), IL-1β expression and the effectiveness of the NF-κB pathway agonist IL-1β against the lung cancer cell lines H838 and H1975. The lung cancer cells H838, H1339, H1650 and H1975 can promote IL-1β secretion by macrophages. In the co-culture of lung cancer cells and macrophages, IL-1β has higher expression than in monoculture. We found no IL-1β expression in a monoculture lung cancer cell supernatant. However, IL-1β was expressed in a macrophage supernatant. This confirms that the IL-1β we detected is secreted by macrophages. Lung cancer cells promote IL-1β secretion by macrophages. In co-culture, the amount of IL-1β secreted is related to the number of macrophages: the number of macrophages decreases with time, and IL-1β secretion decreases accordingly. Interleukin-1β can activate the NF-κB pathway and affect the expression of the pathway components in both H838 and H1975 cells. In H838 cells, IL-1β activated the NF-κB pathway, and downregulation of IκBα, NFκB2 and RelA was observed. In H1975 cells, IL-1β activated the NF-κB pathway, and downregulation of IκBα, IκBε, IKKβ, NFκB1, NFκB2 and RelA (pS529) was observed. Lung cancer cells can stimulate macrophages to increase IL-1β secretion, which can activate the NF-κB pathway in these cells and induce them to produce a more favourable growth environment for their survival. These interactions should be considered when studying and modeling the expression of IL-1β as a potential therapeutic target in lung cancer.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: NF-κB, IL-1β, lung cancer
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 15. Dezember 2021
• 1. Bericht­erstatter:in: Huber, Rudolf Maria