IL-33 Increases Antibacterial Peptide LL-37/CRAMP In Macrophages And Synergistically Affects Lung Cancer Cell Proliferation

Objective: To investigate whether the pro-inflammatory cytokine IL-33 can regulate the expression of antibacterial peptide LL-37/CRAMP in macrophages;and whether LL-37/CRAMP cooperates with IL-33 to mediate the release of inflammatory cytokines in macrophages,thereby affecting the proliferation or invasion of lung cancer cells.Background: Lung cancer is the first cause of cancer-related death,and the persistent inflammation is closely related to the tumorigenesis and progression of lung cancer.Study on the association between inflammation and lung cancer can provide new ideas and new methods for inhibiting the development of lung cancer.The pro-inflammatory cytokine IL-33 is a key "alarmin" to initiate the inflammatory response when the host is injured and infected.In recent years,numerous studies have reported that IL-33 also plays an important role in tumor immunity.Increasing evidence suggests IL-33 is involved in the development of in regulating lung cancer development,but the current opinions about the function and mechanism of IL-33 in lung cancer are still controversial.Meanwhile,antibacterial peptide LL-37/CRAMP also exerts a significant effect on immune responses to lung cancer.LL-37/CRAMP is considered as multifunctional,including antimicrobial activities,angiogenesis and tissue repair.However,it remains unknown how these two molecules affect the immune response and contribute to lung cancer.We also wonder whether there is an immunomodulatory relationship between IL-33 and LL-37/CRAMP in tumor reaction in host macrophages.Therefore,we will investigate whether IL-33 induces the expression of LL-37/CRAMP in macrophages,and whether they can affect the proliferation or invasion of lung cancer cells.Methods and Results:1.The secretion of LL-37 was up-regulated in lung cancer serum samples.Similarly,the expressions of antibacterial peptide LL-37/CRAMP and pro-inflammatory cytokines IL-6 and IL-1β were increased in RAW264.7 macrophages after co-cultured with lung cancer cells.2.IL-33 was capable of up-regulating LL-37/CRAMP secretion in macrophages,resulting in the massive releases of IL-6 and IL-1β.3.LL-37/CRAMP cooperated with IL-33 to increase the phosphorylation of p38 MAPK and NF-κB p65 pathways,then augmented the expression of IL-6 and IL-1β,which resulting in the proliferation of lung cancer cells in vitro.Conclusions: Our results identified that IL-33 synergistically affects the proliferation of lung cancer cells by increasing LL-37/CRAMP levels in macrophages.This study extends our understanding of the immunomodulatory relationship between pro-inflammatory cytokines and antibacterial peptides in the tumor immune response,and offer a novel perspective for controlling the progress of lung cancer.