Decitabine Promotes Modulation in Phenotype and Function of Monocytes and Macrophages That Drive Immune Response Regulation.

Decitabine is an approved hypomethylating agent used for treating hematological malignancies. Although decitabine targets altered cells, epidrugs can trigger immunomodulatory effects, reinforcing the hypothesis of immunoregulation in treated patients. We therefore aimed to evaluate the impact of decitabine treatment on the phenotype and functions of monocytes and macrophages, which are pivotal cells of the innate immunity system. In vitro decitabine administration increased bacterial phagocytosis and IL-8 release, but impaired microbicidal activity of monocytes. In addition, during monocyte-to-macrophage differentiation, treatment promoted the M2-like profile, with increased expression of CD206 and ALOX15. Macrophages also demonstrated reduced infection control when exposed to Mycobacterium tuberculosis in vitro. However, cytokine production remained unchanged, indicating an atypical M2 macrophage. Furthermore, when macrophages were cocultured with lymphocytes, decitabine induced a reduction in the release of inflammatory cytokines such as IL-1ß, TNF-α, and IFN-γ, maintaining IL-10 production, suggesting that decitabine could potentialize M2 polarization and might be considered as a therapeutic against the exacerbated immune response.

Notch signaling pathway in infectious diseases: role in the regulation of immune response.

BACKGROUND: The Notch signaling pathway is a cell signaling system that is conserved in a variety of eukaryotes. Overall, Notch receptors and their ligands are single-pass transmembrane proteins, which often require cell-cell interactions and proteolytic processing to promote signaling. Since its discovery, it has been the subject of extensive research that revealed its importance in several cellular mechanisms, including cell fate determination, hematopoiesis, tissue self-renewal, proliferation, and apoptosis during embryogenesis. Many studies have described the influence of the Notch pathway in modulating the innate and adaptive immune systems. METHODS: We analyzed the literature on the role of the Notch pathway in regulating immune responses during infections, aiming to discuss the importance of establishing a Notch signaling pathway-based approach for predicting the outcome of infectious diseases. CONCLUSION: In this review, we present an overview of evidence that demonstrates the direct and indirect effects of interaction between the Notch signaling pathway and the immune responses against bacterial, viral, fungal, and parasitic infections, as well as the importance of this pathway to predict the outcome of infectious diseases.

The influence of dehydroepiandrosterone on effector functions of neutrophils

Dehydroepiandrosterone (DHEA) is a steroid hormone secreted by the adrenal glands, gonads and brain. It is a precursor to sex hormones and also is known to have immune modulatory activity. However, little is known about the relationship between DHEA and neutrophils and thus our study evaluates the influence of DHEA in the effector functions of neutrophils. Human neutrophils were treated in vitro with DHEA and further infected with Salmonella enterica serovar Typhimurium. The treatment of neutrophils with 0.01 µM of DHEA increased the phagocytosis of Salmonella independent of TLR4 as the treatment did not modulate the TLR4 expression. Additionally, DHEA caused a decrease in ROS (reactive oxygen species) production and did not influence the formation of the neutrophil extracellular trap (NET). Steroid treated neutrophils, infected or stimulated with LPS (lipopolysaccharide), showed reduced production of IL-8, compared to untreated cells. Also, the protein levels of p-NFκB were decreased in neutrophils treated with DHEA, and this reduction could explain the reduced levels of IL-8. These results led us to conclude that the steroid hormone DHEA has important modulatory functions in neutrophils

Immunosenescence in chronic HIV infected patients impairs essential functions of their natural killer cells.

The HIV/AIDS pandemic still represents an important global health issue. There is no sterilizing cure, therefore a continuous treatment is necessary, which caused the emerged idea of HIV as a chronic inflammatory disease that may also affect healthy aging. Considering that the activation profile of some innate cells such as natural killer cells has previously been associated to HIV progression, it remains to be better defined this activation status of NK cells considering the time of HIV infection. In this study, we characterized NK cell phenotype and function during acute and chronic HIV infection and also investigated markers of immunosenescence in these cells. Our results showed that chronic infected patients remained with elevated levels of some plasma inflammatory molecules (IP-10, sCD14) and a concurrent expansion of the non-functional NK cell subset (CD3-CD56-CD16+). NK cells from the chronic infected group displayed an activated profile with higher levels of cytokines and chemokines production (TNF-α, IL-12, IFN-α2, IFN-γ, IL-6, RANTES, MCP-1, IL-10, IL-4 and IL-5). The production of these molecules was positively correlated to the time of infection. Moreover, we noted a possible association of higher global DNA methylation frequency of NK cells in two HIV patients in the advanced stage of disease. Chronic infected patients also showed a trend towards higher production of reactive oxygen species by their NK cells which altogether suggest the evolution of these cells to a senescent state that might be further evaluated.

Pulmonary surfactant phosphatidylcholines induce immunological adaptation of alveolar macrophages.

Pulmonary surfactant plays an important role in lung surface tension, defense against invading pathogens, and immune response. Furthermore, alveolar macrophages (AM) that comprise the front line of immune defense against inhaled microorganisms are covered by a layer of pulmonary fluid. Phosphatidylcholines (PCs), including unsaturated lipids such as 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), are the most prevalent phospholipids in pulmonary surfactant. POPC reacts with ozone to produce 1-palmitoyl-2-(9-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PONPC), a soluble mediator that initiates an inflammatory reaction in the lungs. However, the modulatory effects of POPC and PONPC on biology and activity of AM remain inconclusive. The exposure of AM (cell line AMJ2-C11) to POPC and PONPC was not directly related to the production of inflammatory mediators. However, AM, pre-incubated with POPC or PONPC, showed enhanced response after lipopolysaccharide (LPS) stimulation, and increased the production of nitric oxide and cytokines. This phenomenon was also observed for classical-polarized macrophages (M1). This increment on the production of inflammatory mediators was not associated with macrophage polarization, but with up-regulation of Tlr4 and Myd88 gene expression, which was in accordance with the adaptation of immune cells. This observation was confirmed by the histone acetylation epigenetic pathway. In contrast to the priming effect of POPC on AM activity, a harmful immune response, induced on incubation with PONPC, improved prostaglandin E2 (PGE2) formation, resulting in diminished bacterial phagocytosis. Additionally, PONPC induced production of CXCL1/KC, which potentially mediates neutrophil recruitment and enhances tissue inflammation. These results disclosed another dynamic mechanism by which pulmonary surfactant lipids (natural or oxidized) primed macrophage activity, thus affecting lung host defense.

Plasma Eicosanoid Profile in Plasmodium vivax Malaria: Clinical Analysis and Impacts of Self-Medication.

The participation of cytokines and chemokines in Plasmodium vivax malaria (Pv-malaria) activates the immune response and thus causes the production of several inflammatory mediators. This process is already well-established, but little is known about eicosanoids in malaria physiopathology, especially in regards to inflammation and immunity. Malaria is an acute febrile syndrome similar to any other less important infectious disease and people may self-medicate with any anti-inflammatory drugs in order to cease the recurrent symptoms of the disease. Based on this information, the study describes the eicosanoid profile and its possible influence on the production of cytokines and chemokines in P. vivax infections. In addition, we investigated the influence of self-medication with anti-inflammatory drugs in this immune profile. Twenty-three patients were included in the study, with or without self-medication by anti-inflammatory drugs prior to diagnosis. A total 12 individuals were selected for the control group. Eicosanoid profiles were quantified by HPLC-MS/MS, and cytokines and chemokines by flow cytometry and ELISA. The Pv-malaria infection significantly reduces the production of several lipid mediators, and its action is increased by self-medication. We observed that the eicosanoids we found derive from the lipoxygenase and cyclooxygenase pathways, and present positive and negative correlations with chemokines and cytokines in the follow-up of patients. Our data suggest that self-medication may interfere in the immunological characteristics in P. vivax infection and may modify the follow-up of the disease.

Philadelphia-negative myeloproliferative neoplasms as disorders marked by cytokine modulation.

BACKGROUND: Cytokines are key immune mediators in physiological and disease processes, whose increased levels have been associated with the physiopathology of hematopoietic malignancies, such as myeloproliferative neoplasms. METHODS: This study examined the plasma cytokine profiles of patients with essential thrombocythemia, primary myelofibrosis, polycythemia vera and of healthy subjects, and analyzed correlations with JAK2 V617F status and clinical-hematological parameters. RESULTS: The proinflammatory cytokine levels were increased in myeloproliferative neoplasm patients, and the presence of the JAK2 V617F mutation was associated with high IP-10 levels in primary myelofibrosis patients. CONCLUSIONS: Essential thrombocythemia, primary myelofibrosis, and polycythemia vera patients exhibited different patterns of cytokine production, as revealed by cytokine network correlations. Together, these findings suggest that augmented cytokine levels are associated with the physiopathology of myeloproliferative neoplasms.

Philadelphia-negative myeloproliferative neoplasms as disorders marked by cytokine modulation

ABSTRACT Background: Cytokines are key immune mediators in physiological and disease processes, whose increased levels have been associated with the physiopathology of hematopoietic malignancies, such as myeloproliferative neoplasms. Methods: This study examined the plasma cytokine profiles of patients with essential thrombocythemia, primary myelofibrosis, polycythemia vera and of healthy subjects, and analyzed correlations with JAK2 V617F status and clinical-hematological parameters. Results: The proinflammatory cytokine levels were increased in myeloproliferative neoplasm patients, and the presence of the JAK2 V617F mutation was associated with high IP-10 levels in primary myelofibrosis patients. Conclusions: Essential thrombocythemia, primary myelofibrosis, and polycythemia vera patients exhibited different patterns of cytokine production, as revealed by cytokine network correlations. Together, these findings suggest that augmented cytokine levels are associated with the physiopathology of myeloproliferative neoplasms.

Natural products from cyanobacteria with antimicrobial and antitumor activity.

Cyanobacteria are an important source of structurally bioactive metabolites, with cytotoxic, antiviral, anticancer, antimitotic, antimicrobial, specific enzyme inhibition and immunosuppressive activities. This study focused on the antitumor and antimicrobial activities of intra and extracellular cyanobacterial extracts. A total of 411 cyanobacterial strains were screened for antimicrobial activity using a subset of pathogenic bacteria as target. The in vitro antitumor assays were performed with extracts of 24 strains tested against two murine cancer cell lines (colon carcinoma CT-26 and lung cancer 3LL). Intracellular extracts inhibited 49 and 35% of Gram-negative and Gram-positive pathogenic bacterial growth, respectively. Furthermore, the methanolic intracellular extract of Cylindrospermopsis raciborskii CYP011K and Nostoc sp. CENA69 showed inhibitory activity against the cancer cell lines. The extracellular extract from Fischerella sp. CENA213 and M. aeruginosa NPJB-1 exhibited inhibitory activity against 3LL lung cancer cells at 0.8 µg ml⁻¹ and Oxynema sp. CENA135, Cyanobium sp. CENA154, M. aeruginosa NPJB-1 and M. aeruginosa NPLJ-4 presented inhibitory activity against CT26 colon cancer cells at 0.8 µg ml⁻¹. Other extracts were able to inhibit 3LL cell-growth at higher concentrations (20 µg ml⁻¹) such as Nostoc sp. CENA67, Cyanobium sp. CENA154 and M. aeruginosa NPLJ-4, while CT26 cells were inhibited at the same concentration by Nostoc sp. CENA67 and Fischerella sp. CENA213. These extracts presented very low inhibitory activity on human peripheral blood lymphocytes. The results showed that some cyanobacterial strains are a rich source of natural products with potential for pharmacological and biotechnological applications.