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      Modulation of Cytokines Production by Indomethacin Acute Dose during the Evolution of Ehrlich Ascites Tumor in Mice


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          The aim of the present study was to investigate the influence of a nonselective COX1/COX2 inhibitor (indomethacin) on tumor growth of Ehrlich Ascites Tumor (EAT) in mice, using as parameters the tumor growth and cytokine profile. Mice were inoculated with EAT cells and treated with indomethacin. After 1, 3, 6, 10, and 13 days the animals were evaluated for the secretion of TNF α, IL-1 α, IL-2, IL-4, IL-6, IL-10, and IL-13 and PGE 2 level in peritoneal cavity. The results have shown that EAT induces PGE 2 production and increases tumor cells number from the 10th day. The cytokine profile showed EAT induces production of IL-6 from 10th day and of IL-2 on 13th day; the other studied cytokines were not affected in a significant way. The indomethacin treatment of EAT-bearing mice inhibited the tumor growth and PGE 2 synthesis from the 10th day. In addition, the treatment of EAT-bearing mice with indomethacin has stimulated the IL-13 production and has significantly inhibited IL-6 in the 13th day of tumor growth. Taken together, the results have demonstrated that EAT growth is modulated by PGE 2 and the inhibition of the tumor growth could be partly related to suppression of IL-6 and induction of IL-13.

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          Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer.

          Altered immune, inflammatory, and angiogenesis responses are observed in patients with head and neck squamous cell carcinoma (HNSCC), and many of these responses have been linked with aggressive malignant behavior and a decrease in prognosis. In this study, we examined the hypothesis that HNSCC cells produce cytokines that regulate immune, inflammatory, and angiogenesis responses. We identified important regulatory cytokines in supernatants of well-defined and freshly cultured HNSCC cell lines by ELISA and determined whether these cytokines are detected in tumor cell lines and tissue specimens by immunohistochemistry. The serum concentration of the cytokines and cytokine-dependent acute phase inflammatory responses (i.e., fibrinogen, C-reactive protein, and erythrocyte sedimentation rate) from patients with HNSCC was determined, and the potential relationship of serum cytokine levels to tumor volume was analyzed. Cytokines interleukin (IL)-1alpha, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor were detected in similar concentration ranges in the supernatants of a panel of established University of Michigan squamous cell carcinoma (UM-SCC) cell lines and supernatants of freshly isolated primary HNSCC cultures. Evidence for the expression of IL-1alpha, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, and VEGF in HNSCC cells within tumor specimens in situ was obtained by immunohistochemistry. In a prospective comparison of the cytokine level and cytokine-inducible acute-phase proteins in serum, we report that cytokines IL-6, IL-8, and VEGF were detected at higher concentrations in the serum of patients with HNSCC compared with patients with laryngeal papilloma or age-matched control subjects (at P < 0.05). The serum concentrations of IL-8 and VEGF were found to be weakly correlated with large primary tumor volume (R2 = 0.2 and 0.4, respectively). Elevated IL-1- and IL-6-inducible acute-phase responses were also detected in cancer patients but not in patients with papilloma or control subjects (at P < 0.05). We therefore conclude that cytokines important in proinflammatory and proangiogenic responses are detectable in cell lines, tissue specimens, and serum from patients with HNSCC. These cytokines may increase the pathogenicity of HNSCC and prove useful as biomarkers or targets for therapy.
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            Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators.

            Chronic inflammation and presence of inflammatory cells, primarily macrophages, at tumor sites are highly associated with specific malignancies. In these cases, the inflammatory milieu is overloaded with mediators that suppress immune activities at many levels: recognition of tumor-associated antigens, activation, the actual cytolysis of tumor cells and more. Local suppression of leukocyte functions at the inflammatory tumor site further contributes to profound immunosuppression of potential anti-tumor immune functions. The present review discusses the inflammatory setup in tumors and the factors inducing the presence of detrimental inflammatory macrophages at tumor sites. Moreover, the different mediators that contribute to inflammation-associated immune suppression, including primarily cytokines and chemokines but also prostaglandins and oxidants, are described. Bearing in mind the notion that under specific conditions the inflammatory mediators clearly contribute to malignancy, while in others they may exert surveillance missions against tumor cells, the potential therapeutic value of the inflammatory components is discussed.
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              Microenvironment-derived IL-1 and IL-17 interact in the control of lung metastasis.

              Inflammatory cytokines modulate immune responses in the tumor microenvironment during progression/metastasis. In this study, we have assessed the role of IL-1 and IL-17 in the control of antitumor immunity versus progression in a model of experimental lung metastasis, using 3LL and B16 epithelial tumor cells. The absence of IL-1 signaling or its excess in the lung microenvironment (in IL-1β and IL-1R antagonist knockout [KO] mice, respectively) resulted in a poor prognosis and reduced T cell activity, compared with WT mice. In IL-1β KO mice, enhanced T regulatory cell development/function, due to a favorable in situ cytokine network and impairment in APC maturation, resulted in suppressed antitumor immunity, whereas in IL-1R antagonist KO mice, enhanced accumulation and activity of myeloid-derived suppressor cells were found. Reduced tumor progression along with improved T cell function was found in IL-17 KO mice, compared with WT mice. In the microenvironment of lung tumors, IL-1 induces IL-17 through recruitment of γ/δ T cells and their activation for IL-17 production, with no involvement of Th17 cells. These interactions were specific to the microenvironment of lung tumors, as in intrafootpad tumors in IL-1/IL-17 KO mice, different patterns of invasiveness were observed and no IL-17 could be locally detected. The results highlight the critical and unique role of IL-1, and cytokines induced by it such as IL-17, in determining the balance between inflammation and antitumor immunity in specific tumor microenvironments. Also, we suggest that intervention in IL-1/IL-17 production could be therapeutically used to tilt this balance toward enhanced antitumor immunity.

                Author and article information

                Mediators Inflamm
                Mediators Inflamm
                Mediators of Inflammation
                Hindawi Publishing Corporation
                12 August 2015
                : 2015
                : 924028
                1Department of Pathology, School of Medicine, São Paulo State University (UNESP), 18618-970 Botucatu, SP, Brazil
                2Laboratory of Glycobiology, Carlos Chagas Filho Biophysics Institute (IBCCF), Federal University of Rio de Janeiro (UFRJ), 21941-902 Rio de Janeiro, RJ, Brazil
                3Applied Pharmacology and Toxicology Laboratory, School of Veterinary Medicine, University of São Paulo, 05508-900 São Paulo, SP, Brazil
                Author notes
                *Luciana Boffoni Gentile: luboffoni@ 123456yahoo.com.br

                Academic Editor: Mirella Giovarelli

                Copyright © 2015 Luciana Boffoni Gentile et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 25 May 2015
                : 9 July 2015
                : 12 July 2015
                Research Article



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