miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1

Abstract Dendritic cells (DCs) are potent antigen-presenting cells derived from hematopoietic progenitor cells and circulating monocytes. To investigate the role of microRNAs (miRNAs) during DC differentiation, maturation, and function, we profiled miRNA expression in human monocytes, immature DCs (imDCs), and mature DCs (mDCs). Stage-specific, differential expression of 27 miRNAs was found during monocyte differentiation into imDCs and mDCs. Among them, decreased miR-221 and increased miR-155 expression correlated with p27kip1 accumulation in DCs. Silencing of miR-221 or overexpressing of miR-155 in DCs resulted in p27kip1 protein increase and DC apoptosis. Moreover, mDCs from miR-155−/− mice were less apoptotic than those from wild-type mice. Silencing of miR-155 expression had little effect on DC maturation but reduced IL-12p70 production, whereas miR-155 overexpression in mDCs enhanced IL-12p70 production. Kip1 ubiquitination-promoting complex 1, suppressor of cytokine signaling 1, and CD115 (M-CSFR) were functional targets of miR-155. Furthermore, we provide evidence that miR-155 indirectly regulated p27kip1 protein level by targeting Kip1 ubiquitination-promoting complex 1. Thus, our study uncovered miRNA signatures during monocyte differentiation into DCs and the new regulatory role of miR-221 and miR-155 in DC apoptosis and IL-12p70 production.

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Absence of suppressor of cytokine signaling 2 turns cardiomyocytes unresponsive to LIF-dependent increases in Ca2+ levels

AJP Cell Physiology ◽

10.1152/ajpcell.00004.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. C478-C486 ◽

Cited By ~ 1

Author(s):

Cibele Rocha-Resende ◽

Itamar Couto Guedes de Jesus ◽

Danilo Roman-Campos ◽

Artur S. Miranda ◽

Fabiana Alves ◽

...

Keyword(s):

Leukemia Inhibitory Factor ◽

Inhibitory Factor ◽

Cytokine Signaling ◽

Wild Type ◽

Suppressor Of Cytokine Signaling ◽

Gp130 Receptor ◽

Intracellular Ca ◽

Full Activation

Little is known regarding the role of suppressor of cytokine signaling (SOCS) in the control of cytokine signaling in cardiomyocytes. We investigated the consequences of SOCS2 ablation for leukemia inhibitory factor (LIF)-induced enhancement of intracellular Ca2+ ([Ca2+]i) transient by performing experiments with cardiomyocytes from SOCS2-knockout (ko) mice. Similar levels of SOCS3 transcripts were seen in cardiomyocytes from wild-type and SOCS2-ko mice, while SOCS1 mRNA was reduced in SOCS2-ko. Immunoprecipitation experiments showed increased SOCS3 association with gp130 receptor in SOCS2-ko myocytes. Measurements of Ca2+ in wild-type myocytes exposed to LIF showed a significant increase in the magnitude of the Ca2+ transient. This change was absent in LIF-treated SOCS2-ko cells. LIF activation of ERK and STAT3 was observed in both wild-type and SOCS2-ko cells, indicating that in SOCS2-ko, LIF receptors were functional, despite the lack of effect in the Ca2+ transient. In wild-type cells, LIF-induced increase in [Ca2+]i and phospholamban Thr17 [PLN(Thr17)] phosphorylation was inhibited by KN-93, indicating a role for CaMKII in LIF-induced Ca2+ raise. LIF-induced phosphorylation of PLN(Thr17) was abrogated in SOCS2-ko myocytes. In wild-type cardiomyocytes, LIF treatment increased L-type Ca2+ current ( ICa,L), a key activator of CaMKII in response to LIF. Conversely, SOCS2-ko myocytes failed to activate ICa,L in response to LIF, providing a rationale for the lack of LIF effect on Ca2+ transient. Our data show that absence of SOCS2 turns cardiomyocytes unresponsive to LIF-induced [Ca2+] raise, indicating that endogenous levels of SOCS2 are crucial for full activation of LIF signaling in the heart.

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The role of CXC-chemokine receptor CXCR2 and suppressor of cytokine signaling-3 (SOCS-3) in renal cell carcinoma

BMC Cancer ◽

10.1186/1471-2407-14-149 ◽

2014 ◽

Vol 14 (1) ◽

Cited By ~ 15

Author(s):

Anastasios Stofas ◽

Georgia Levidou ◽

Christina Piperi ◽

Christos Adamopoulos ◽

Georgia Dalagiorgou ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Chemokine Receptor ◽

Renal Cell ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Cxc Chemokine ◽

Chemokine Receptor Cxcr2

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Role of Suppressor of Cytokine Signaling 2 during the development and resolution of an experimental arthritis

Cellular Immunology ◽

10.1016/j.cellimm.2021.104476 ◽

2022 ◽

pp. 104476

Author(s):

Allysson Cramer ◽

Izabela Galvão ◽

Nathália Venturini de Sá ◽

Paulo Gaio ◽

Natália Fernanda de Melo Oliveira ◽

...

Keyword(s):

Experimental Arthritis ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling

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Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽

10.1161/circ.118.suppl_18.s_467-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Christina Grothusen ◽

Harald Schuett ◽

Stefan Lumpe ◽

Andre Bleich ◽

Silke Glage ◽

...

Keyword(s):

Foam Cell ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cell Formation ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

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Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar

Development ◽

10.1242/dev.129.10.2541 ◽

2002 ◽

Vol 129 (10) ◽

pp. 2541-2553 ◽

Cited By ~ 4

Author(s):

Johanna Laurikkala ◽

Johanna Pispa ◽

Han-Sung Jung ◽

Pekka Nieminen ◽

Marja Mikkola ◽

...

Keyword(s):

Signaling Pathway ◽

Hair Follicles ◽

Wild Type ◽

Mutant Mouse Embryos ◽

Anhidrotic Ectodermal Dysplasia ◽

Embryonic Morphogenesis ◽

Hair Follicle Development ◽

And Function ◽

Insight Into

X-linked and autosomal forms of anhidrotic ectodermal dysplasia syndromes (HED) are characterized by deficient development of several ectodermal organs, including hair, teeth and exocrine glands. The recent cloning of the genes that underlie these syndromes, ectodysplasin (ED1) and the ectodysplasin A receptor (EDAR), and their identification as a novel TNF ligand-receptor pair suggested a role for TNF signaling in embryonic morphogenesis. In the mouse, the genes of the spontaneous mutations Tabby (Ta) and downless (dl) were identified as homologs of ED1 and EDAR, respectively. To gain insight into the function of this signaling pathway in development of skin and hair follicles, we analyzed the expression and regulation of Eda and Edar in wild type as well as Tabby and Lef1 mutant mouse embryos. We show that Eda and Edar expression is confined to the ectoderm and occurs in a pattern that suggests a role of ectodysplasin/Edar signaling in the interactions between the ectodermal compartments and the formation and function of hair placodes. By using skin explant cultures, we further show that this signaling pathway is intimately associated with interactions between the epithelial and mesenchymal tissues. We also find that Ta mutants lack completely the placodes of the first developing tylotrich hairs, and that they do not show patterned expression of placodal genes, including Bmp4, Lef1, Shh, Ptch and Edar, and the genes for β-catenin and activin A. Finally, we identified activin as a mesenchymal signal that stimulates Edar expression and WNT as a signal that induces Eda expression, suggesting a hierarchy of distinct signaling pathways in the development of skin and hair follicles. In conclusion, we suggest that Eda and Edar are associated with the onset of ectodermal patterning and that ectodysplasin/edar signaling also regulates the morphogenesis of hair follicles.

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TLR7 modulating B-cell immune responses in the spleen of C57BL/6 mice infected with Schistosoma japonicum

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009943 ◽

2021 ◽

Vol 15 (11) ◽

pp. e0009943

Author(s):

Haixia Wei ◽

Hongyan Xie ◽

Jiale Qu ◽

Anqi Xie ◽

Shihao Xie ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Gene Knockout ◽

Innate Immune ◽

Wild Type ◽

Cell Responses ◽

Splenic Cells ◽

And Function ◽

Egg Antigen

B cells played an important role in Schistosoma infection-induced diseases. TLR7 is an intracellular member of the innate immune receptor. The role of TLR7 on B cells mediated immune response is still unclear. Here, C57BL/6 mice were percutaneously infected by S. japonicum for 5–6 weeks. The percentages and numbers of B cells increased in the infected mice (p < 0.05), and many activation and function associated molecules were also changed on B cells. More splenic cells of the infected mice expressed TLR7, and B cells were served as the main cell population. Moreover, a lower level of soluble egg antigen (SEA) specific antibody and less activation associated molecules were found on the surface of splenic B cells from S. japonicum infected TLR7 gene knockout (TLR7 KO) mice compared to infected wild type (WT) mice (p < 0.05). Additionally, SEA showed a little higher ability in inducing the activation of B cells from naive WT mice than TLR7 KO mice (p < 0.05). Finally, the effects of TLR7 on B cells are dependent on the activation of NF-κB p65. Altogether, TLR7 was found modulating the splenic B cell responses in S. japonicum infected C57BL/6 mice.

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Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17-1 cells) enriched in the bone marrow of patients with myeloma

Blood ◽

10.1182/blood-2008-03-143222 ◽

2008 ◽

Vol 112 (7) ◽

pp. 2878-2885 ◽

Cited By ~ 127

Author(s):

Kavita M. Dhodapkar ◽

Scott Barbuto ◽

Phillip Matthews ◽

Anjli Kukreja ◽

Amitabha Mazumder ◽

...

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

Th17 Cells ◽

T Helper ◽

Tumor Bed ◽

Distinct Lineage ◽

Human Dendritic Cells ◽

Antigen Presenting ◽

Dc Maturation

Abstract IL17-producing (Th17) cells are a distinct lineage of T helper cells that regulate immunity and inflammation. The role of antigen-presenting cells in the induction of Th17 cells in humans remains to be fully defined. Here, we show that human dendritic cells (DCs) are efficient inducers of Th17 cells in culture, including antigen-specific Th17 cells. Although most freshly isolated circulating human Th17 cells secrete IL17 alone or with IL2, those induced by DCs are polyfunctional and coexpress IL17 and IFNγ (Th17-1 cells). The capacity of DCs to expand Th17-1 cells is enhanced upon DC maturation, and mature DCs are superior to monocytes for the expansion of autologous Th17 cells. In myeloma, where tumors are infiltrated by DCs, Th17 cells are enriched in the bone marrow relative to circulation. Bone marrow from patients with myeloma contains a higher proportion of Th17-1 cells compared with the marrow in preneoplastic gammopathy (monoclonal gammopathy of undetermined significance [MGUS]). Uptake of apoptotic but not necrotic myeloma tumor cells by DCs leads to enhanced induction of Th17-1 cells. These data demonstrate the capacity of DCs to induce expansion of polyfunctional IL17-producing T cells in humans, and suggest a role for DCs in the enrichment of Th17-1 cells in the tumor bed.

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PSGL-1 regulates platelet P-selectin-mediated endothelial activation and shedding of P-selectin from activated platelets

Thrombosis and Haemostasis ◽

10.1160/th07-03-0207 ◽

2007 ◽

Vol 98 (10) ◽

pp. 806-812 ◽

Cited By ~ 46

Author(s):

Vandana Dole ◽

Wolfgang Bergmeier ◽

Ian Patten ◽

Junichi Hirahashi ◽

Tanya Mayadas ◽

...

Keyword(s):

Endothelial Activation ◽

Leukocyte Rolling ◽

Wild Type ◽

Platelet Surface ◽

Activated Platelets ◽

And Function ◽

Body Secretion

SummaryWe have previously shown that activated platelets in circulation stimulate release of endothelial Weibel-Palade bodies thus increasing leukocyte rolling in venules. P-selectin on the activated platelets mediates adhesion to leukocytes via PSGL-1 and is rapidly shed into plasma. We were interested in studying the role of PSGL-1 in regulating expression and function of platelet P-selectin. We show here that PSGL-1 is critical for the activation of endothelial cells in venules of mice infused with activated platelets. The interaction of platelet P-selectin with PSGL-1 is also required for P-selectin shedding, as P-selectin was retained significantly longer on the surface of activated platelets infused into PSGL-1-/- compared to wild-type mice. The leukocyte integrin αMβ2 (Mac-1) was not required for P-selectin shedding. In addition to shedding, P-selectin can be downregulated from the platelet surface through internalization and this is the predominant mechanism in the absence of PSGL-1. We demonstrate that leukocyte- neutrophil elastase,known to cleave P-selectin in vitro, is not the major sheddase for P-selectin in vivo. In conclusion, interaction of platelet P-selectin with PSGL-1 is crucial for activation of the endothelium andWeibel-Palade body secretion. The interaction with PSGL-1 also results in rapid shedding of P-selectin thus downregulating the inflammatory potential of the platelet.

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