1.Interleukin-17 Indirectly Promotes M2 Macrophage Differentiation through Stimulation of COX-2/PGE2 Pathway in the Cancer Cells.
Qingli LI ; Lunxu LIU ; Qiuyang ZHANG ; Sen LIU ; Dongxia GE ; Zongbing YOU
Cancer Research and Treatment 2014;46(3):297-306
PURPOSE: Interleukin-17 (IL-17) is a proinflammatory cytokine that plays important roles in inflammation, autoimmunity, and cancer. The purpose of this study was to determine if IL-17 indirectly regulates macrophage differentiation through up-regulation of cyclooxygenase-2 (COX-2) expression in the cancer cell lines. MATERIALS AND METHODS: Human cervical cancer HeLa, human lung cancer A549, and mouse prostate cancer Myc-CaP/CR cell lines were treated with recombinant IL-17; Western blot analysis, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction analysis were utilized to examine the cellular responses. RESULTS: IL-17 up-regulated expression of COX-2 mRNA and protein in HeLa, A549, and Myc-CaP/CR cell lines. IL-17's effects were mediated through nuclear factor-kappaB and ERK1/2 signaling pathways as the inhibitors of these pathways could inhibit IL-17-induced COX-2 expression. The conditional medium obtained from the cancer cells contained prostaglandin E2, the levels of which were increased by IL-17 treatment. When treated with the conditional medium, particularly with the IL-17-induced conditional medium, mouse RAW264.7 macrophages and human THP-1 monocytes expressed higher levels of IL-10 (a marker of M2 macrophages) than inducible nitric oxide synthase or tumor necrosis factor alpha (markers of M1 macrophages). In contrast, when RAW264.7 and THP-1 cells were treated directly with IL-17, expression of these marker genes was not markedly changed. CONCLUSION: The results of this study suggest that IL-17 indirectly promotes M2 macrophage differentiation through stimulation of the COX-2/PGE2 pathway in the cancer cells, thus IL-17 plays an indirect role in regulating the tumor immune microenvironment.
Animals
;
Autoimmunity
;
Blotting, Western
;
Cell Line
;
Cyclooxygenase 2
;
Dinoprostone
;
Enzyme-Linked Immunosorbent Assay
;
Humans
;
Inflammation
;
Interleukin-10
;
Interleukin-17*
;
Lung Neoplasms
;
Macrophages*
;
Mice
;
Monocytes
;
Nitric Oxide Synthase Type II
;
Prostatic Neoplasms
;
Real-Time Polymerase Chain Reaction
;
RNA, Messenger
;
Tumor Microenvironment
;
Tumor Necrosis Factor-alpha
;
Up-Regulation
;
Uterine Cervical Neoplasms