IL-10: Master Switch from Tumor-Promoting Inflammation to Antitumor Immunity
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Abstract Human cancer is characterized by deficits in antigen-specific immunity and intratumoral CD8+ T cells. On the other hand, inflammatory macrophages and mediators of chronic inflammation are highly prevalent in patients with late-stage cancer. Intratumoral T-cell deficiency and chronic inflammation have been linked independently to a poor prognosis in patients with cancer, and therapeutic approaches to overcome either pathology separately are in clinical testing. The anti-inflammatory cytokine interleukin (IL)-10 suppresses macrophage and proinflammatory Th17 T-cell responses by inhibiting the inflammatory cytokines IL-6 and IL-12/23. Corroborating the anti-inflammatory action of IL-10, deficiency in IL-10 leads to a stimulation of inflammatory responses and inflammatory bowel disease. The anti-inflammatory role of IL-10 fostered the assumption that IL-10 undermines the immune response to cancer. However, mice and humans deficient in IL-10 signaling develop tumors spontaneously and at high rates. Overexpression of IL-10 in models of human cancer or treatment with a pegylated IL-10 (PEG-IL-10) led to tumor rejection and long-lasting tumor immunity. IL-10 stimulates cytotoxicity of CD8+ T cells and the expression of IFN-γ in CD8+ T cells. IL-10–induced tumor rejections are dependent on the expression of IFN-γ and granzymes in tumor-resident CD8+ T cells and the upregulation of MHC molecules. These findings reconcile earlier clinical data, which showed that recombinant IL-10 increased IFN-γ and granzymes in the blood of treated individuals. PEG-IL-10 is therefore a unique therapeutic agent, which simultaneously stimulates antitumor immunity and inhibits tumor-associated inflammation. Cancer Immunol Res; 2(3); 194–9. ©2014 AACR.Keywords:
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Proinflammatory cytokines traditionally thought to be derived exclusively from the immune system and were therefore considered to be primarily responsible for initiating inflammatory in the myocardium. The effects of Proinflammatory Cytokines in the heart were discussed.
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Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1) have been found to be elevated in bronchoalveolar lavage (BAL) fluid and in plasma from patients with acute respiratory distress syndrome (ARDS). In order to measure the balance of proinflammatory cytokines and their inhibitors, we quantified the upregulation of intercellular adhesion molecules (ICAM-1) induced by ARDS BAL fluids in human alveolar type II-like (A459) cells, and defined proinflammatory activity as the amount of ICAM-1 induced by the SAL fluids. Proinflammatory activity was detected in 77% of the SAL fluids sampled during the first week of ARDS, was found maximal during the 3 first days after onset of ARDS, and was significantly greater than in BAL specimens from at risk patients. Blocking experiments with specific inhibitors of TNF and IL-1 added to the BAL fluids indicated that the bioactivity measured was mainly due to IL-1. In contrast, proinflammatory activity of conditioned supernates from endotoxin-treated alveolar macrophages was mostly due to TNF. Using a bioassay that measures balance of cytokines with their inhibitors, our results indicate that the net proinflammatory activity in ARDS BAL fluids is attributable to IL-1 and not to TNF.
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Abstract Objectives The study was to explore the influence of microRNA (miR)-345-3p on proinflammatory cytokines in patients with rheumatoid arthritis (RA). Methods A total of 32 RA patients and 32 healthy patients were enrolled. Proinflammatory factors in patients’ serum were detected by ELISA, and miR-345-3p was detected by RT-qPCR. The correlation between miR-345-3p expression and proinflammatory factors in RA patients was analyzed. The diagnostic value of miR-345-3p and proinflammatory factors in RA patients was analyzed by receiver operating curve diagnosis. The predictive value of miR-345-3p levels and proinflammatory factors in RA patients was analyzed by multivariate Cox regression. HFLS-RA and HFLS cells were cultured, in which miR-345-3p and proinflammatory cytokines were detected by RT-qPCR. Cell proliferation and apoptosis were determined by CCK-8 and flow cytometry, respectively. Results MiR-345-3p was lowly expressed in the serum of RA patients. MiR-345-3p and proinflammatory factors were of diagnostic and predictive values in RA. Elevated miR-345-3p restrained the production of proinflammatory factors of HFLS-RA cells, improved cell proliferation, and reduced apoptosis. Conclusion MiR-345-3p is a potential biomarker and ameliorates RA by reducing the release of proinflammatory cytokines.
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The brain's response to ischemic injury is an acute and long-term inflammatory process. This process involves activation of resident cells (mainly microglia, hematogenous macrophages), production of proinflammatory mediators and infiltration of various proinflammatory cells (mainly neutrophils and lymphocytes). These cells play an essential role in ischemic brain tissue by releasing either proinflammatory or anti-inflammatory mediators at different time points. However, the exact pathogenesis of proinflammatory or anti-inflammatory genes in this process has not yet been elucidated. This review aims to investigate the inflammatory process of stroke, especially the role of proinflammatory and anti-inflammatory genes in the pathogenesis of stroke. We also summarize the current clinical trials of drugs that target the inflammatory mechanism for intervention.
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Abstract Despite great success in cancer immunotherapy, immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy. Accumulating evidence suggests that the tumor immune microenvironment plays a critical role in anti-cancer immunity, which may result in immune checkpoint blockade therapy being ineffective, in addition to other novel immunotherapies in cancer patients. In the present review, we discuss the deficiencies of current cancer immunotherapies. More importantly, we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance, immunological evasion, and the potential for their further translation into clinical practice. Based on their general targetability in clinical therapy, we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets. Targeting the tumor immune microenvironment, alone or in combination with immune checkpoint-targeting drugs, might benefit cancer patients in the future.
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Nanoscience has long been lauded as a method through which tumor-associated barriers could be overcome. As successful as cancer immunotherapy has been, limitations associated with the tumor microenvironment or side effects of systemic treatment have become more apparent. In this Review, we seek to lay out the therapeutic challenges associated with the tumor microenvironment and the ways in which nanoscience is being applied to remodel the tumor microenvironment and increase the susceptibility of many cancer types to immunotherapy. We detail the nanomedicines on the cutting edge of cancer immunotherapy and how their interactions with the tumor microenvironment make them more effective than systemically administered immunotherapies.
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Summary: Cytotoxic lymphocytes are armed with granules that are released in the granule‐exocytosis pathway to kill tumor cells and virus‐infected cells. Cytotoxic granules contain the pore‐forming protein perforin and a family of structurally homologues serine proteases called granzymes. While perforin facilitates the entry of granzymes into a target cell, the latter initiate distinct apoptotic routes. Granzymes are also implicated in extracellular functions such as extracellular matrix degradation, immune regulation, and inflammation. The family of human granzymes consists of five members, of which granzyme A and B have been studied most extensively. Recently, elucidation of the specific characteristics of the other three human granzymes H, K, and M, also referred to as orphan granzymes, have started. In this review, we summarize and discuss what is currently known about the biology of the human orphan granzymes.
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Proinflammatory reaction by the body occurs acutely in response to injury that is considered primarily beneficial. However, sustained proinflammatory cytokines observed with chronic pathologies such as metabolic syndrome, cancer, and arthritis are detrimental and in many cases is a major cardiovascular risk factor. Proinflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor α (TNFα) have long been implicated in cardiovascular risk and considered to be a major underlying cause for heart failure (HF). The failure of the anti-TNFα therapy for HF indicates our elusive understanding on the dichotomous role of proinflammatory cytokines on acutely beneficial effects versus long-term deleterious effects. Despite these well-described observations, less is known about the mechanistic underpinnings of proinflammatory cytokines especially TNFα in pathogenesis of HF. Increasing evidence suggests the existence of an active cross-talk between the TNFα receptor signaling and G-protein-coupled receptors such as β-adrenergic receptor (βAR). Given that βARs are the key regulators of cardiac function, the review will discuss the current state of understanding on the role of proinflammatory cytokine TNFα in regulating βAR function.
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