Interleukin-17 Indirectly Promotes M2 Macrophage Differentiation through Stimulation of COX-2/PGE2 Pathway in the Cancer Cells

Abstract

PurposeInterleukin-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 MethodsHuman 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.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 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 α (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.ConclusionThe 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.

Interleukin-17A Promotes Arginase-1 Production and 2,4-Dinitrochlorobenzene-Induced Acute Hyperinflammation in Human Papillomavirus E7 Oncoprotein-Expressing Skin

“…Our observation that blockade of IL-17A caused a significant reduction in arginase-1 is consistent with a recent study which suggested that IL-17A indirectly mediates arginase-1 production in macrophages via the induction of cyclooxygenase-2 production by HeLa, a human cervical cancer cell line [17]. Moreover, IL-17A has been shown to mediate arginase-1 induction by promoting infiltration of inflammatory monocytes to the site of inflammation [26].…”

“…Since IL-17A has been shown to induce arginase-1 expression by macrophages in recent studies [16,17], we next investigated whether IL-17A played a role in the induction of arginase in our model. Depletion of IL-17A with neutralising antibody, in contrast to depletion of IL-10 and IL-4, significantly reduced the observed level of arginase activity (fig.…”

“…In a murine asthma model, Th2 cytokines induced arginase-1 and allergic airway inflammation [14]. In addition to Th2 cytokines, IL-17A, an important cytokine of innate immunity, has also been shown to induce arginase-1 production in inflammatory macrophages in a model of Leishmania amazonensis infection [15] in vascular inflammation [16] and in a tumour environment [17]. …”

Genetic basis of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs

“…Another proinflammatory cytokine is IL-17, which can stimulate COX-2 expression [73]. MAFs of three SNPs on the promoter of IL-17 receptor achain (À1075 A>G, À947 A>G, À50C>T) were lower in NERD patients than in ATA [74].…”

CD4, IL-17, and COX-2 Are Associated With Subclinical Inflammation in Malar Melasma

“…16 Studies have suggested that IL-17 and COX-2 show a reciprocal effect on each other but have not been previously evaluated in melasma. 17,18 Therefore, we sought to characterize inflammation in this condition by evaluating the cellular infiltrate, the expression of acute and chronic immune inflammatory mediators, and nonimmune inflammation mechanism such as COX-2.…”