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Nfat5/Stat3 Interaction Mediates Synergism Of High Salt With Il-17 Towards Induction Of Vegf-A Expression In Breast Cancer Cells, Suneetha Amara, Dalal Alotaibi, Venkataswarup Tiriveedhi
Nfat5/Stat3 Interaction Mediates Synergism Of High Salt With Il-17 Towards Induction Of Vegf-A Expression In Breast Cancer Cells, Suneetha Amara, Dalal Alotaibi, Venkataswarup Tiriveedhi
Biology Faculty Research
Chronic inflammation has been considered an important player in cancer proliferation and progression. High salt (sodium chloride) levels have been considered a potent inducer of chronic inflammation. In the present study, the synergistic role of high salt with interleukin (IL)‑17 towards induction of the inflammatory and angiogenic stress factor vascular endothelial growth factor (VEGF)‑A was investigated. Stimulation of MCF-7 breast cancer cells with high salt (0.2 M NaCl) and sub‑minimal IL‑17 (1 ng/ml) enhanced the expression of VEGF-A (2.9 and 2.6-fold, respectively, P<0.05) compared with untreated cells. Furthermore, co‑treatment with both high salt and sub‑minimal IL‑17 led to a 5.9‑fold increase in VEGF‑A expression (P<0.01), thus suggesting a synergistic role of these factors. VEGF‑A promoter analysis and specific small interfering RNA knock‑down of transcription factors revealed that high salt induced VEGF‑A expression through nuclear factor of activated T‑cells (NFAT)5, while IL‑17 induced VEGF‑A expression via signal transducer and activator of transcription (STAT)3 signaling mechanisms. Treatment of normal human aortic endothelial cells with the supernatant of activated MCF‑7 cells enhanced cell migration and induced expression of migration‑specific factors, including vascular cell adhesion protein, β1 integrin and cluster of differentiation 31. These data suggest that high salt levels synergize with pro‑inflammatory IL‑17 to potentially induce cancer progression and metastasis through VEGF‑A expression. Therefore, low‑salt diet, anti‑NFAT5 and anti‑STAT3 therapies may provide novel avenues for enhanced efficiency of the current cancer therapy.
High Salt Induces Anti-Inflammatory Mφ2-Like Phenotype In Peripheral Macrophages, Suneetha Amara, Margaret M. Whalen, Venkataswarup Tiriveedhi
High Salt Induces Anti-Inflammatory Mφ2-Like Phenotype In Peripheral Macrophages, Suneetha Amara, Margaret M. Whalen, Venkataswarup Tiriveedhi
Chemistry Faculty Research
Macrophages play a critical role in inflammation and antigen-presentation. Abnormal macrophage function has been attributed in autoimmune diseases and cancer progression. Recent evidence suggests that high salt tissue micro-environment causes changes in macrophage activation. In our current report, we studied the role of extracellular sodium chloride on phenotype changes in peripheral circulating monocyte/macrophages collected from healthy donors. High salt (0.2M NaCl vs basal 0.1M NaCl) treatment resulted in a decrease in MΦ1 macrophage phenotype (CD11b+CD14highCD16low) from 77.4±6.2% (0.1M) to 29.3±5.7% (0.2M, p<0.05), while there was an increase in MΦ2 macrophage phenotype (CD11b+ CD14lowCD16high) from 17.2±5.9% (0.1M) to 67.4±9.4% (0.2M, p<0.05). ELISA-based cytokine analysis demonstrated that high salt treatment induced decreased expression of in the MΦ1 phenotype specific pro-inflammatory cytokine, TNFα (3.3 fold), IL-12 (2.3 fold), CCL-10 (2 fold) and CCL-5 (3.8 fold), but conversely induced an enhanced expression MΦ2-like phenotype specific anti-inflammatory cytokine, IL-10, TGFβ, CCL-17 (3.7 fold) and CCR-2 (4.3 fold). Further high salt treatment significantly decreased phagocytic efficiency of macrophages and inducible nitric oxide synthetase expression. Taken together, these data suggest that high salt extracellular environment induces an anti-inflammatory MΦ2-like macrophage phenotype with poor phagocytic and potentially reduced antigen presentation capacity commonly found in tumor microenvironment.
Sodium Channel Γenac Mediates Il-17 Synergized High Salt Induced Inflammatory Stress In Breast Cancer Cells, Suneetha Amara, Michael T. Ivy, Elbert L. Myles, Venkataswarup Tiriveedhi
Sodium Channel Γenac Mediates Il-17 Synergized High Salt Induced Inflammatory Stress In Breast Cancer Cells, Suneetha Amara, Michael T. Ivy, Elbert L. Myles, Venkataswarup Tiriveedhi
Biology Faculty Research
Chronic inflammation is known to play a critical role in the development of cancer. Recent evidence suggests that high salt in the tissue microenvironment induces chronic inflammatory milieu. In this report, using three breast cancer-related cell lines, we determined the molecular basis of the potential synergistic inflammatory effect of sodium chloride (NaCl) with interleukin-17 (IL-17). Combined treatment of high NaCl (0.15M) with sub-effective IL-17 (0.1nM) induced enhanced growth in breast cancer cells along with activation of reactive nitrogen and oxygen (RNS/ROS) species known to promote cancer. Similar effect was not observed with equi-molar mannitol. This enhanced of ROS/RNS activity correlates …