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      IL-17 induces macrophages to M2-like phenotype via NF-κB

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          Abstract

          Background

          Tumor-associated macrophage (TAM) is emerging as one of the important complications in cancer promotion. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, plays an active role in promoting M2 macrophage differentiation (TAMs are M2-like phenotypes). In this study, we aimed to evaluate that IL-17 stimulates key phenotypic and functional signatures of M2 macrophages associated with cancer progression in non-small-cell lung cancer (NSCLC) patients.

          Patients and methods

          The markers and cytokines of M2 macrophages were detected in THP-1-derived macrophages and mouse peritoneal macrophages treated with IL-17. The activation of nuclear factor kappa B (NF-κB) and nuclear localization of p65 in IL-17-treated cells were investigated. The BAY11-7082 inhibitor and the siRNA of p65 were used to block the NF-κB activation. A total of 85 patients who underwent surgery for histologically verified NSCLC were enrolled in this study. The expression of IL-17 and M2 macrophage markers were assessed by immunostaining. Survivals were estimated using the Kaplan–Meier method.

          Results

          The CD163 and CD206 cell surface markers and transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF) and IL-10 of M2 macrophages were significantly increased in IL-17-treated THP-1-derived macrophages in a dose-dependent manner. IL-17 increased the mRNA levels of Arginase I and Fizz1, the phosphorylation of IkBα and nuclear localization of p65 (a subunit of NF-κB). The BAY11-7082 abrogated IL-17-induced CD206 and CD163 expression, TGF-β, VEGF, IL-10, Arginase I and Fizz1 expression and p65 nuclear translocation. Further experiments showed that IL-17 induced the expression of CD206, CD163, Arginase I, Fizz1 and Ym1 in mouse peritoneal macrophages that were inhibited by siRNA of p65. The immunostaining experiments on human NSCLC tissues indicated that high IL-17 expression was significantly correlated with CD163 and c-Maf. The intratumoral IL-17+ CD163+ c-Maf+ cells were associated with NSCLC progression.

          Conclusion

          IL-17 stimulated macrophages to M2-like phenotypes via NF-κB activation. IL-17 may be a potential therapeutic target for NSCLC.

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          Most cited references25

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          Ubiquitin signalling in the NF-kappaB pathway.

          The transcription factor NF-kappaB (nuclear factor kappa enhancer binding protein) controls many processes, including immunity, inflammation and apoptosis. Ubiquitination regulates at least three steps in the NF-kappaB pathway: degradation of IkappaB (inhibitor of NF-kappaB), processing of NF-kappaB precursors, and activation of the IkappaB kinase (IKK). Recent studies have revealed several enzymes involved in the ubiquitination and deubiquitination of signalling proteins that mediate IKK activation through a degradation-independent mechanism.
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            Macrophage Polarisation: an Immunohistochemical Approach for Identifying M1 and M2 Macrophages

            Macrophage polarization is increasingly recognised as an important pathogenetic factor in inflammatory and neoplastic diseases. Proinflammatory M1 macrophages promote T helper (Th) 1 responses and show tumoricidal activity. M2 macrophages contribute to tissue repair and promote Th2 responses. CD68 and CD163 are used to identify macrophages in tissue sections. However, characterisation of polarised macrophages in situ has remained difficult. Macrophage polarisation is regulated by transcription factors, pSTAT1 and RBP-J for M1, and CMAF for M2. We reasoned that double-labelling immunohistochemistry for the detection of macrophage markers together with transcription factors may be suitable to characterise macrophage polarisation in situ. To test this hypothesis, we have studied conditions associated with Th1- and Th2-predominant immune responses: infectious mononucleosis and Crohn’s disease for Th1 and allergic nasal polyps, oxyuriasis, wound healing and foreign body granulomas for predominant Th2 response. In all situations, CD163+ cells usually outnumbered CD68+ cells. Moreover, CD163+ cells, usually considered as M2 macrophages, co-expressing pSTAT1 and RBP-J were found in all conditions examined. The numbers of putative M1 macrophages were higher in Th1- than in Th2-associated diseases, while more M2 macrophages were seen in Th2- than in Th1 related disorders. In most Th1-related diseases, the balance of M1 over M2 cells was shifted towards M1 cells, while the reverse was observed for Th2-related conditions. Hierarchical cluster analysis revealed two distinct clusters: cluster I included Th1 diseases together with cases with high numbers of CD163+pSTAT1+, CD68+pSTAT1+, CD163+RBP-J+ and CD68+RBP-J+ macrophages; cluster II comprised Th2 conditions together with cases displaying high numbers of CD163+CMAF+ and CD68+CMAF+ macrophages. These results suggest that the detection of pSTAT1, RBP-J, and CMAF in the context of CD68 or CD163 expression is a suitable tool for the characterisation of macrophage polarisation in situ. Furthermore, CD163 cannot be considered a reliable M2 marker when used on its own.
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              Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer.

              Macrophages are the dominant leukocyte population found in the tumor microenvironment. Accumulating evidence suggests that these tumor-associated macrophages (TAMs) actively promote all aspects of tumor initiation, growth, and development. However, TAMs are not a single uniform population; instead, they are composed of multiple distinct pro- and anti-tumoral subpopulations with overlapping features depending on a variety of external factors. Defining and differentiating these subsets remains a challenging work-in-progress. These difficulties are apparent in prognostic studies in lung cancer that initially demonstrated conflicting evidence regarding the significance of TAMs but which have more recently clarified and confirmed the clinical importance of these subsets through improved phenotypic capabilities. Thus, these cells represent potential targets for cancer therapeutic initiatives through translational approaches. In this review, we summarize the current understanding of how the tumor microenvironment takes advantage of macrophage plasticity to mold an immunosuppressive population, the phenotypic heterogeneity of TAMs, and their link to prognosis in human lung cancer.
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                Author and article information

                Journal
                Cancer Manag Res
                Cancer Manag Res
                Cancer Management and Research
                Cancer Management and Research
                Dove Medical Press
                1179-1322
                2018
                04 October 2018
                : 10
                : 4217-4228
                Affiliations
                [1 ]Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China, yuyan@ 123456ems.hrbmu.edu.cn
                [2 ]Department of Cardiology, The First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin, People’s Republic of China
                Author notes
                Correspondence: Yan Yu, Department of Medical Oncology, Harbin Medical University Cancer Hospital, No 150 Haping Road, Harbin 150081, People’s Republic of China, Tel/fax +86 451 8629 8727, Email yuyan@ 123456ems.hrbmu.edu.cn
                [*]

                These authors contributed equally to this work

                Article
                cmar-10-4217
                10.2147/CMAR.S174899
                6177522
                30323677
                bd53e29e-03a1-4f20-9e3a-fc1af99d8c5a
                © 2018 Shen et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Categories
                Original Research

                Oncology & Radiotherapy
                il-17,m2 macrophages,nf-κb,non-small-cell lung cancer,survival
                Oncology & Radiotherapy
                il-17, m2 macrophages, nf-κb, non-small-cell lung cancer, survival

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