Interleukin-17 Indirectly Promotes M2 Macrophage Differentiation through Stimulation of COX-2/PGE2 Pathway in the Cancer Cells
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PurposeInterleukin-17 (IL-17) is a proinflammatory cytokine that plays important roles ininflammation, autoimmunity, and cancer. The purpose of this study was to determineif IL-17 indirectly regulates macrophage differentiation through up-regulation ofcyclooxygenase-2 (COX-2) expression in the cancer cell lines. Materials and MethodsHuman cervical cancer HeLa, human lung cancer A549, and mouse prostate cancerMyc-CaP/CR cell lines were treated with recombinant IL-17; Western blot analysis,enzyme-linked immunosorbent assay, and quantitative real-time polymerase chainreaction analysis were utilized to examine the cellular responses. ResultsIL-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-κB andERK1/2 signaling pathways as the inhibitors of these pathways could inhibit IL-17-induced COX-2 expression. The conditional medium obtained from the cancer cellscontained prostaglandin E2, the levels of which were increased by IL-17 treatment. When treated with the conditional medium, particularly with the IL-17-induced conditionalmedium, mouse RAW264.7 macrophages and human THP-1 monocytes expressedhigher levels of IL-10 (a marker of M2 macrophages) than inducible nitricoxide synthase or tumor necrosis factor α (markers of M1 macrophages). In contrast,when RAW264.7 and THP-1 cells were treated directly with IL-17, expression of thesemarker genes was not markedly changed. ConclusionThe results of this study suggest that IL-17 indirectly promotes M2 macrophagedifferentiation 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.
Abstract
PurposeInterleukin-17 (IL-17) is a proinflammatory cytokine that plays important roles ininflammation, autoimmunity, and cancer. The purpose of this study was to determineif IL-17 indirectly regulates macrophage differentiation through up-regulation ofcyclooxygenase-2 (COX-2) expression in the cancer cell lines. Materials and MethodsHuman cervical cancer HeLa, human lung cancer A549, and mouse prostate cancerMyc-CaP/CR cell lines were treated with recombinant IL-17; Western blot analysis,enzyme-linked immunosorbent assay, and quantitative real-time polymerase chainreaction analysis were utilized to examine the cellular responses. ResultsIL-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-κB andERK1/2 signaling pathways as the inhibitors of these pathways could inhibit IL-17-induced COX-2 expression. The conditional medium obtained from the cancer cellscontained prostaglandin E2, the levels of which were increased by IL-17 treatment. When treated with the conditional medium, particularly with the IL-17-induced conditionalmedium, mouse RAW264.7 macrophages and human THP-1 monocytes expressedhigher levels of IL-10 (a marker of M2 macrophages) than inducible nitricoxide synthase or tumor necrosis factor α (markers of M1 macrophages). In contrast,when RAW264.7 and THP-1 cells were treated directly with IL-17, expression of thesemarker genes was not markedly changed. ConclusionThe results of this study suggest that IL-17 indirectly promotes M2 macrophagedifferentiation 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.
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