IL-6 produced by prostate epithelial cells stimulated with Trichomonas vaginalis promotes proliferation of prostate cancer cells by inducing M2 polarization of THP-1-derived macrophages

Abstract

Trichomonas vaginalis (Tv), a protozoan parasite causing sexually-transmitted disease, has been detected in tissue of prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer (PCa). IL-6, a mediator of chronic inflammation, induces the progression of prostate cancer, and influences the polarization of M2 macrophages, which are the main tumor-associated macrophages. We investigated whether IL-6 produced by human prostate epithelial cells stimulated with Tv induces the M2 polarization of THP-1-derived macrophages, which in turn promotes the progression of PCa. Conditioned medium was prepared from Tvinfected (TCM) and uninfected (CM) prostate epithelial cells (RWPE-1). Thereafter conditioned medium was prepared from macrophages after incubation with CM (M-CM) or TCM (M-TCM). RWPE-1 cells infected with Tv produced IL-6 and chemokines such as CCL2 and CXCL8. When human macrophages were treated with conditioned medium of RWPE-1 cells co-cultured with Tv (TCM), they became polarized to M2-like macrophages as indicated by the production of IL-10 and TGF-β, and the expression of CD36 and arginase-1, which are M2 macrophage markers. Moreover, proliferation of the M2-like macrophages was also increased by TCM. Blockade of IL-6 signaling with IL-6 receptor antibody and JAK inhibitor (Ruxolitinib) inhibited M2 polarization of THP-1-derived macrophages and proliferation of the macrophages. To assess the effect of crosstalk between macrophages and prostate epithelial cells inflamed by Tv infection on the growth of prostate cancer (PCa) cells, PC3, DU145 and LNCaP cells were treated with conditioned medium from THP-1-derived macrophages stimulated with TCM (M-TCM). Proliferation and migration of the PCa cells were significantly increased by the M-TCM. Our findings suggest that IL-6 produced in response to Tv infection of the prostate has an important effect on the tumor microenvironment by promoting progression of PCa cells following induction of M2 macrophage polarization.

KLHDC7B-DT aggravates pancreatic ductal adenocarcinoma development via inducing cross-talk between cancer cells and macrophages

“…Intriguingly, we also found that IL-6 secreted by PDAC cells and induced by KLHDC7B-DT could also activate STAT3 and AKT signaling in macrophages in a paracrine manner. The activation of STAT3 and AKT signaling has been frequently revealed to induce macrophages M2 polarization [38][39][40]. Consistently, in this study, we found that KLHDC7B-DT induced macrophages M2 polarization through promoting IL-6 secretion in the in vitro coculture system of PDAC cells and macrophages.…”

“…IL-6 neutralizing antibodies reduced alternatively activated M2 macrophages population, but did not affect classically activated M1 macrophages population in glioblastoma [64]. IL-6 produced by prostate epithelial cells induced macrophages M2 polarization in prostate cancer [40]. Here, we also showed that IL-6 induced macrophages M2 polarization in PDAC.…”

“…PTEN-PI3K-AKT signaling and STAT3 signaling have been revealed to be involved in the macrophages M2 polarization [38][39][40]. IL-6 is also frequently reported to activate AKT and STAT3 [41,42].…”

Association of Female Genital Schistosomiasis With the Cervicovaginal Microbiota and Sexually Transmitted Infections in Zambian Women

“…To disentangle the association between S. haematobium , T. vaginalis , and HIV-1, future studies using sensitive molecular methods for both parasites are needed. Additionally, macrophage polarization can be influenced by the local immune environment, schistosomes, and T. vaginalis [ 53 , 54 ]. We have previously shown that, compared with FGS-negative women, high-burden FGS is associated with higher concentrations of cervicovaginal Th2 cytokines [ 32 ].…”

Application of Anti-Inflammatory Agents in Prostate Cancer

“…Human prostate carcinoma-associated fibroblasts and prostate cancer cells orchestrate and enhance TAM and MDSC recruitment to prostate tumors as well as M2-like TAM differentiation by the chemokines CCL2, CXCL12, and IL-6 during cancer progression [ 76 , 122 ]. Sexually transmitted disease-associated inflammation facilitates IL-6 production by prostate epithelial cells, which induces M2-like TAM polarization [ 123 ]. Furthermore, MDSC and tumor cell cross-talk enhances IL-6 production within tumor microenvironment [ 124 ], while IL-10, produced by MDSCs, increases M2-like TAMs [ 125 , 126 , 127 ].…”