Purpose: Acute and persistent inflammation plays an important role in the establishment and progression of the pancreatic ductal adenocarcinoma (PDAC). Modified macrophages, tumour associated macrophages (TAMs) are key contributors to the survival, growth, and metastatic behaviour of the PDAC cells, by interacting with them. Central to the role of inflammation and TAMs, lies the NLRP3 inflammasome. The crosstalk between PDAC cells and TAMs has been postulated to regulate the NLRP3 inflammasome activity and the subsequent associated inflammation in the tumour microenvironment, which, in turn affects the crosstalk and the survival, proliferation and metastatic potential of PDAC cells. This study investigated the effects of LPS-stimulated inflammation on cell proliferation, levels of pro-inflammatory cytokines and the NLRP3 inflammasome pathway in a co-culture model using PDAC cells and macrophages, in the with or without MCC950, a NLRP3 specific inhibitor.Methods: The effects of LPS-stimulated inflammation were tested on two PDAC cell lines (Panc 10.05 and SW 1990) co-cultured with RAW 264.7 macrophages. Cell proliferation was determined using the MTT assay. Levels of pro-inflammatory cytokines, IL-1β and TNF-α were determined by ELISA. Western blot analyses were used to examine the expression of NLRP3 in both PDAC cells and macrophages.Results: The crosstalk between PDAC cell lines and macrophages under LPS-stimulation led to pro-inflammatory microenvironment, as evidenced by high levels of secreted IL-1β and TNF-α. The crosstalk was also responsible for regulating the NLRP3 expression in both PDAC cells and macrophages as well as promoting PDAC cell proliferation. Inhibition of the NLRP3 inflammasome by MCC950, counteracted the effects of LPS-stimulation on the crosstalk. However, MCC950 differentially modified the viability of the metastatic vs primary PDAC cells lines. Conclusion: The stimulation by LPS increased PDAC cells viability by modulating the crosstalk between PDAC cells and RAW 264.7 macrophages (in a co-culture model) that results in the activation of NLRP inflammasome. The specific inhibition of NLRP inflammasome by MCC950 effectively counteracted the LPS-stimulated inflammation.
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