Browsing by Subject "immunomodulation"

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  • Costa de Oliveira, Regiane; Soares Pontes, Gemilson; Kostyuk, Aleksandr; Coutinho Camargo, Gabriel B.; Dhyani, Anamika; Shvydenko, Tetiana; Shvydenko, Kostiantyn; Grafov, Andriy (2020)
    Cancer still remains a major public health concern around the world and the search for new potential antitumor molecules is essential for fighting the disease. This study evaluated the anticancer and immunomodulatory potential of the newly synthetized ellipticine derivate: sodium bromo-5,11-dimethyl-6H-pyrido[4,3-b]carbazole-7-sulfonate (Br-Ell-SO3Na). It was prepared by the chlorosulfonation of 9-bromoellipticine. The ellipticine-7-sulfonic acid itself is not soluble, but its saponification with sodium hydroxide afforded a water-soluble sodium salt. The cytotoxicity of Br-Ell-SO3Na was tested against cancerous (K562 cell line) and non-cancerous cells (Vero cell line and human peripheral blood mononuclear cells (PBMC)) using a Methylthiazoletetrazolium (MTT) assay. Cell cycle arrest was assessed by flow cytometry and the immunomodulatory activity was analyzed through an enzyme-linked immunosorbent assay (ELISA)(.) The results showed that the Br-Ell-SO3Na molecule has specific anticancer activity (IC50 = 35 mu M) against the K562 cell line, once no cytotoxicity effect was verified against non-cancerous cells. Cell cycle analysis demonstrated that K562 cells treated with Br-Ell-SO3Na were arrested in the phase S. Moreover, the production of IL-6 increased and the expression of IL-8 was inhibited in the human PBMC treated with Br-Ell-SO3Na. The results demonstrated that Br-Ell-SO3Na is a promising anticancer molecule attested by its noteworthy activity against the K562 tumor cell line and immunomodulatory activity in human PBMC cells.
  • Kinaret, Pia Anneli Sofia; Scala, Giovanni; Federico, Antonio; Sund, Jukka; Greco, Dario (2020)
    Toxic effects of certain carbon nanomaterials (CNM) have been observed in several exposure scenarios both in vivo and in vitro. However, most of the data currently available has been generated in a high-dose/acute exposure setup, limiting the understanding of their immunomodulatory mechanisms. Here, macrophage-like THP-1 cells, exposed to ten different CNM for 48 h in low-cytotoxic concentration of 10 mu g mL(-1), are characterized by secretion of different cytokines and global transcriptional changes. Subsequently, the relationships between cytokine secretion and transcriptional patterns are modeled, highlighting specific pathways related to alternative macrophage activation. Finally, time- and dose-dependent activation of transcription and secretion of M1 marker genes IL-1 beta and tumor necrosis factor, and M2 marker genes IL-10 and CSF1 is confirmed among the three most responsive CNM, with concentrations of 5, 10, and 20 mu g mL(-1) at 24, 48, and 72 h of exposure. These results underline CNM effects on the formation of cell microenvironment and gene expression leading to specific patterns of macrophage polarization. Taken together, these findings imply that, instead of a high and toxic CNM dose, a sub-lethal dose in controlled exposure setup can be utilized to alter the cell microenvironment and program antigen presenting cells, with fascinating implications for novel therapeutic strategies.
  • Holopainen, Minna; Impola, Ulla; Lehenkari, Petri; Laitinen, Saara; Kerkela, Erja (2020)
    Human mesenchymal stromal/stem cells (hMSCs) show great promise in cell therapy due to their immunomodulatory properties. The overall immunomodulatory response of hMSCs resembles the resolution of inflammation, in which lipid mediators and regulatory macrophages (Mregs) play key roles. We investigated the effect of hMSC cell-cell contact and secretome on macrophages polarized and activated toward Mreg phenotype. Moreover, we studied the effect of supplemented polyunsaturated fatty acids (PUFAs): docosahexaenoic acid (DHA) and arachidonic acid, the precursors of lipid mediators, on hMSC immunomodulation. Our results show that unlike hMSC cell-cell contact, the hMSC secretome markedly increased the CD206 expression in both Mreg-polarized and Mreg-activated macrophages. Moreover, the secretome enhanced the expression of programmed death-ligand 1 on Mreg-polarized macrophages and Mer receptor tyrosine kinase on Mreg-activated macrophages. Remarkably, these changes were translated into improvedCandida albicansphagocytosis activity of macrophages. Taken together, these results demonstrate that the hMSC secretome promotes the immunoregulatory and proresolving phenotype of Mregs. Intriguingly, DHA supplementation to hMSCs resulted in a more potentiated immunomodulation with increased CD163 expression and decreased gene expression of matrix metalloproteinase 2 in Mreg-polarized macrophages. These findings highlight the potential of PUFA supplementations as an easy and safe method to improve the hMSC therapeutic potential.
  • Hiippala, Kaisa; Kainulainen, Veera; Suutarinen, Maiju; Heini, Tuomas; Bowers, Jolene R.; Jasso-Selles, Daniel; Lemmer, Darrin; Valentine, Michael; Barnes, Riley; Engelthaler, David M.; Satokari, Reetta (2020)
    Altered intestinal microbiota is associated with systemic and intestinal diseases, such as inflammatory bowel disease (IBD). Dysbiotic microbiota with enhanced proinflammatory capacity is characterized by depletion of anaerobic commensals, increased proportion of facultatively anaerobic bacteria, as well as reduced diversity and stability. In this study, we developed a high-throughput in vitro screening assay to isolate intestinal commensal bacteria with anti-inflammatory capacity from a healthy fecal microbiota transplantation donor. Freshly isolated gut bacteria were screened for their capacity to attenuate Escherichia coli lipopolysaccharide (LPS)-induced interleukin 8 (IL-8) release from HT-29 cells. The screen yielded a number of Bacteroides and Parabacteroides isolates, which were identified as P. distasonis, B. caccae, B. intestinalis, B. uniformis, B. fragilis, B. vulgatus and B. ovatus using whole genome sequencing. We observed that a cell-cell contact with the epithelium was not necessary to alleviate in vitro inflammation as spent culture media from the isolates were also effective and the anti-inflammatory action did not correlate with the enterocyte adherence capacity of the isolates. The anti-inflammatory isolates also exerted enterocyte monolayer reinforcing action and lacked essential genes to synthetize hexa-acylated, proinflammatory lipid A, part of LPS. Yet, the anti-inflammatory effector molecules remain to be identified. The Bacteroides strains isolated and characterized in this study have potential to be used as so-called next-generation probiotics.
  • Hepo-oja, Pilvi (Helsingin yliopisto, 2020)
    Fecal microbiota transplantation (FMT) is used to treat recurrent Clostridioides difficile infection (rCDI), and its potential as a treatment for other inflammatory conditions, like inflammatory bowel diseases (IBD), or irritable bowel syndrome (IBS), has been extensively studied lately. It has been noticed that some bacteria in fecal transplants do not require physical contact with intestinal epithelium to alleviate inflammation, and extracellular vesicles (EVs) have been proposed to carry the anti-inflammatory properties of those beneficial bacteria. In this thesis project, an isolation protocol was set up to isolate EVs from two fecal-originated Bacteroides isolates, Bacteroides ovatus and Bacteroides vulgatus, which had shown anti-inflammatory potential in previous studies. Isolation of EVs succeeded, and both isolates were confirmed to produce EVs. To study the anti-inflammatory potential, human colon epithelial cells (HT-29) were treated with several dilutions of isolated EVs, and then challenged with lipopolysaccharide (LPS) to induce inflammation. Amount of produced interleukin (IL-) 8 was measured as a marker of inflammation. EVs of both Bacteroides isolates continuously showed anti-inflammatory potential, but statistically significant conclusions could not be made. EVs have a potential to be used as a treatment in different inflammatory conditions and as adjuvant factors in synthetic FMT. To study the immunomodulatory potential of EVs of Bacteroides species more, proteomic analysis of contents of EVs, as well as potential to improve intestinal barrier are suggested. Also, testing the ability to alleviate production of other inflammatory markers could reveal more anti-inflammatory potential.
  • Tigistu-Sahle, Feven; Lampinen, Milla; Kilpinen, Lotta; Holopainen, Minna; Lehenkari, Petri; Laitinen, Saara; Käkelä, Reijo (2017)
    High arachidonic acid (20:4n-6) and low n-3 PUFA levels impair the capacity of cultured human bone marrow mesenchymal stromal cells (hBMSCs) to modulate immune functions. The capacity of the hBMSCs to modify PUFA structures was found to be limited. Therefore, different PUFA supplements given to the cells resulted in very different glycerophospholipid (GPL) species profiles and substrate availability for phospholipases, which have preferences for polar head group and acyl chains when liberating PUFA precursors for production of lipid mediators. When supplemented with 20:4n-6, the cells increased prostaglandin E2 secretion. However, they elongated 20:4n-6 to the less active precursor, 22:4n-6, and also incorporated it into triacylglycerols, which may have limited the proinflammatory signaling. The n-3 PUFA precursor, 18:3n-3, had little potency to reduce the GPL 20:4n-6 content, while the eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acid supplements efficiently displaced the 20:4n-6 acyls, and created diverse GPL species substrate pools allowing attenuation of inflammatory signaling.(Jlr) The results emphasize the importance of choosing appropriate PUFA supplements for in vitro hBMSC expansion and suggests that for optimal function they require an exogenous fatty acid source providing 20:5n-3 and 22:6n-3 sufficiently, but 20:4n-6 moderately, which calls for specifically designed optimal PUFA supplements for the cultures.