Gross karyotypic and phenotypic alterations among different progenies of the candida glabrata cbs138/atcc2001 reference strain

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Leukocyte Associated Immunoglobulin Like Receptor 1 Regulation and Function on Monocytes and Dendritic Cells During Inflammation

Inhibitory receptors are crucial immune regulators and are essential to prevent exacerbated responses, thus contributing to immune homeostasis. Leukocyte associated immunoglobulin like receptor 1 (LAIR-1) is an immune inhibitory receptor which has collagen and collagen domain containing proteins as ligands. LAIR-1 is broadly expressed on immune cells and has a large availability of ligands in both circulation and tissues, implicating a need for tight regulation of this interaction. In the current study, we sought to examine the regulation and function of LAIR-1 on monocyte, dendritic cell (DC) and macrophage subtypes, using different in vitro models. We found that LAIR-1 is highly expressed on intermediate monocytes as well as on plasmacytoid DCs. LAIR-1 is also expressed on skin immune cells, mainly on tissue CD14(+) cells, macrophages and CD1c(+) DCs. In vitro, monocyte and type-2 conventional DC stimulation leads to LAIR-1 upregulation, which may reflect the importance of LAIR-1 as negative regulator under inflammatory conditions. Indeed, we demonstrate that LAIR-1 ligation on monocytes inhibits toll like receptor (TLR)4 and Interferon (IFN)-alpha- induced signals. Furthermore, LAIR-1 is downregulated on GM-CSF and IFN-gamma monocyte-derived macrophages and monocyte-derived DCs. In addition, LAIR-1 triggering during monocyte derived-DC differentiation results in significant phenotypic changes, as well as a different response to TLR4 and IFN-alpha stimulation. This indicates a role for LAIR-1 in skewing DC function, which impacts the cytokine expression profile of these cells. In conclusion, we demonstrate that LAIR-1 is consistently upregulated on monocytes and DC during the inflammatory phase of the immune response and tends to restore its expression during the resolution phase. Under inflammatory conditions, LAIR-1 has an inhibitory function, pointing toward to a potential intervention opportunity targeting LAIR-1 in inflammatory conditions

The natural organosulfur compound dipropyltetrasulfide prevents HOCL-induced systemic sclerosis in the mouse

PublishedArticleIntroduction: The aim of this study was to test the naturally occurring organosulfur compound dipropyltetrasulfide (DPTTS) found in plants, which has antibiotic and anti-cancer properties, as a treatment of HOCl-induced systemic sclerosis in the mouse. Methods: The pro-oxidative, anti-proliferative and cytotoxic effects of DPTTS were evaluated ex vivo on fibroblasts from normal and HOCl-mice. In vivo, the anti-fibrotic and immunomodulating properties of DPTTS were evaluated in the skin and lungs of HOCl-mice. Results: H2O2 production was higher in fibroblasts derived from HOCl-mice than in normal fibroblasts (P<0.05). DPTTS did not increase H2O2 production in normal fibroblasts, but DPTTS dose-dependently increased H2O2 production in HOCl-fibroblasts (P<0.001 with 40μM DPTTS). Because H2O2 reached a lethal threshold in cells from HOCl-mice, the anti-proliferative, cytotoxic and pro-apoptotic effects of DPTTS were significantly higher in HOCl-fibroblasts than for normal fibroblasts. In vivo, DPTTS decreased dermal thickness (P<0.001), collagen content in skin (P<0.01) and lungs (P<0.05), SMA (P<0.01) and pSMAD2/3 (P<0.01) expression in skin, formation of advanced oxidation protein products and anti-DNA topoisomerase-1 antibodies in serum (P<0.05) versus untreated HOCl- mice. Moreover, in HOCl-mice, DPTTS reduced splenic B cell counts (P<0.01), the proliferative rates of B-splenocytes stimulated by lipopolysaccharide (P<0.05) and T-splenocytes stimulated by anti-CD3/CD28 mAb (P<0.001). Ex vivo, it also reduced the production of IL-4 and IL-13 by activated T cells (P<0.05 in both cases). Conclusions: The natural organosulfur compound DPTTS prevents skin and lung fibrosis in the mouse through the selective killing of diseased fibroblasts and its immunomodulating properties. DPTTS may be a potential treatment of Systemic sclerosis.This work was supported by European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 215009 RedCat for financial support. The authors are grateful to Ms Agnes for her excellent typing of the manuscript

Angiopoietin-2 Promotes Inflammatory Activation in Monocytes of Systemic Sclerosis Patients

Angiopoietin-2 (Ang-2), a ligand of the tyrosine kinase receptor Tie2, is essential for vascular development and blood vessel stability and is also involved in monocyte activation. Here, we examined the role of Ang-2 on monocyte activation in patients with systemic sclerosis (SSc). Ang-2 levels were measured in serum and skin of healthy controls (HCs) and SSc patients by ELISA and array profiling, respectively. mRNA expression of ANG2 was analyzed in monocytes, dermal fibroblasts, and human pulmonary arterial endothelial cells (HPAECs) by quantitative PCR. Monocytes were stimulated with Ang-2, or with serum from SSc patients in the presence of a Tie2 inhibitor or an anti-Ang2 neutralizing antibody. Interleukin (IL)-6 and IL-8 production was analyzed by ELISA. Ang-2 levels were elevated in the serum and skin of SSc patients compared to HCs. Importantly, serum Ang-2 levels correlated with clinical disease parameters, such as skin involvement. Lipopolysaccharide (LPS) LPS, R848, and interferon alpha2a (IFN-alpha) stimulation up-regulated the mRNA expression of ANG2 in monocytes, dermal fibroblasts, and HPAECs. Finally, Ang-2 induced the production of IL-6 and IL-8 in monocytes of SSc patients, while the inhibition of Tie2 or the neutralization of Ang-2 reduced the production of both cytokines in HC monocytes stimulated with the serum of SSc patients. Therefore, Ang-2 induces inflammatory activation of SSc monocytes and neutralization of Ang-2 might be a promising therapeutic target in the treatment of SSc

Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor alpha via MAP3K8

Dendritic cells (DCs) constantly sample peripheral tissues for antigens, which are subsequently ingested to derive peptides for presentation to T cells in lymph nodes. To do so, DCs have to traverse many different tissues with varying oxygen tensions. Additionally, DCs are often exposed to low oxygen tensions in tumors, where vascularization is lacking, as well as in inflammatory foci, where oxygen is rapidly consumed by inflammatory cells during the respiratory burst. DCs respond to oxygen levels to tailor immune responses to such low-oxygen environments. In the present study, we identified a mechanism of hypoxia-mediated potentiation of release of tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory cytokine with important roles in both anti-cancer immunity and autoimmune disease. We show in human monocyte-derived DCs (moDCs) that this potentiation is controlled exclusively via the p38/mitogen-activated protein kinase (MAPK) pathway. We identified MAPK kinase kinase 8 (MAP3K8) as a target gene of hypoxia-induced factor (HIF), a transcription factor controlled by oxygen tension, upstream of the p38/MAPK pathway. Hypoxia increased expression of MAP3K8 concomitant with the potentiation of TNF-alpha secretion. This potentiation was no longer observed upon siRNA silencing of MAP3K8 or with a small molecule inhibitor of this kinase, and this also decreased p38/MAPK phosphorylation. However, expression of DC maturation markers CD83, CD86, and HLA-DR were not changed by hypoxia. Since DCs play an important role in controlling T-cell activation and differentiation, our results provide novel insight in understanding T-cell responses in inflammation, cancer, autoimmune disease and other diseases where hypoxia is involved

Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor α via MAP3K8

Dendritic cells (DCs) constantly sample peripheral tissues for antigens, which are subsequently ingested to derive peptides for presentation to T cells in lymph nodes. To do so, DCs have to traverse many different tissues with varying oxygen tensions. Additionally, DCs are often exposed to low oxygen tensions in tumors, where vascularization is lacking, as well as in inflammatory foci, where oxygen is rapidly consumed by inflammatory cells during the respiratory burst. DCs respond to oxygen levels to tailor immune responses to such low-oxygen environments. In the present study, we identified a mechanism of hypoxia-mediated potentiation of release of tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine with important roles in both anti-cancer immunity and autoimmune disease. We show in human monocyte-derived DCs (moDCs) that this potentiation is controlled exclusively via the p38/mitogen-activated protein kinase (MAPK) pathway. We identified MAPK kinase kinase 8 (MAP3K8) as a target gene of hypoxia-induced factor (HIF), a transcription factor controlled by oxygen tension, upstream of the p38/MAPK pathway. Hypoxia increased expression of MAP3K8 concomitant with the potentiation of TNF-α secretion. This potentiation was no longer observed upon siRNA silencing of MAP3K8 or with a small molecule inhibitor of this kinase, and this also decreased p38/MAPK phosphorylation. However, expression of DC maturation markers CD83, CD86, and HLA-DR were not changed by hypoxia. Since DCs play an important role in controlling T-cell activation and differentiation, our results provide novel insight in understanding T-cell responses in inflammation, cancer, autoimmune disease and other diseases where hypoxia is involved

Strains used in this study.

<p>Strains used in this study.</p