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  • The American Association of Immunologists  (5)
  • Adamopoulos, Iannis E.  (5)
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  • The American Association of Immunologists  (5)
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  • 1
    Online Resource
    Online Resource
    Ca2+-Dependent Regulation of NFATc1 via KCa3.1 in Inflammatory Osteoclastogenesis
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 2 ( 2018-01-15), p. 749-757
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 2 ( 2018-01-15), p. 749-757
    Abstract: In inflammatory arthritis, the dysregulation of osteoclast activity by proinflammatory cytokines, including TNF, interferes with bone remodeling during inflammation through Ca2+-dependent mechanisms causing pathological bone loss. Ca2+-dependent CREB/c-fos activation via Ca2+-calmodulin kinase IV (CaMKIV) induces transcriptional regulation of osteoclast-specific genes via NFATc1, which facilitate bone resorption. In leukocytes, Ca2+ regulation of NFAT-dependent gene expression oftentimes involves the activity of the Ca2+-activated K+ channel KCa3.1. In this study, we evaluate KCa3.1 as a modulator of Ca2+-induced NFAT-dependent osteoclast differentiation in inflammatory bone loss. Microarray analysis of receptor activator of NF-κB ligand (RANKL)-activated murine bone marrow macrophage (BMM) cultures revealed unique upregulation of KCa3.1 during osteoclastogenesis. The expression of KCa3.1 in vivo was confirmed by immunofluorescence staining on multinucleated cells at the bone surface of inflamed mouse joints. Experiments on in vitro BMM cultures revealed that KCa3.1−/− and TRAM-34 treatment significantly reduced the expression of osteoclast-specific genes (p & lt; 0.05) alongside decreased osteoclast formation (p & lt; 0.0001) in inflammatory (RANKL+TNF) and noninflammatory (RANKL) conditions. In particular, live cell Ca2+ imaging and Western blot analysis showed that TRAM-34 pretreatment decreased transient RANKL-induced Ca2+ amplitudes in BMMs by ∼50% (p & lt; 0.0001) and prevented phosphorylation of CaMKIV. KCa3.1−/− reduced RANKL+/−TNF-stimulated phosphorylation of CREB and expression of c-fos in BMMs (p & lt; 0.01), culminating in decreased NFATc1 protein expression and transcriptional activity (p & lt; 0.01). These data indicate that KCa3.1 regulates Ca2+-dependent NFATc1 expression via CaMKIV/CREB during inflammatory osteoclastogenesis in the presence of TNF, corroborating its role as a target candidate for the treatment of bone erosion in inflammatory arthritis.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1701170
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    IL-23 Is Critical for Induction of Arthritis, Osteoclast Formation, and Maintenance of Bone Mass
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 187, No. 2 ( 2011-07-15), p. 951-959
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 187, No. 2 ( 2011-07-15), p. 951-959
    Abstract: The role of IL-23 in the development of arthritis and bone metabolism was studied using systemic IL-23 exposure in adult mice via hydrodynamic delivery of IL-23 minicircle DNA in vivo and in mice genetically deficient in IL-23. Systemic IL-23 exposure induced chronic arthritis, severe bone loss, and myelopoiesis in the bone marrow and spleen, which resulted in increased osteoclast differentiation and systemic bone loss. The effect of IL-23 was partly dependent on CD4+ T cells, IL-17A, and TNF, but could not be reproduced by overexpression of IL-17A in vivo. A key role in the IL-23–induced arthritis was made by the expansion and activity of myeloid cells. Bone marrow macrophages derived from IL-23p19−/− mice showed a slower maturation into osteoclasts with reduced tartrate-resistant acid phosphatase-positive cells and dentine resorption capacity in in vitro osteoclastogenesis assays. This correlated with fewer multinucleated osteoclast-like cells and more trabecular bone volume and number in 26-wk-old male IL-23p19−/− mice compared with control animals. Collectively, our data suggest that systemic IL-23 exposure induces the expansion of a myeloid lineage osteoclast precursor, and targeting IL-23 pathway may combat inflammation-driven bone destruction as observed in rheumatoid arthritis and other autoimmune arthritides.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1003986
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
    detail.hit.zdb_id: 1475085-5
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Crosstalk among IL-23 and DNAX Activating Protein of 12 kDa–Dependent Pathways Promotes Osteoclastogenesis
    The American Association of Immunologists ; 2015
    In:  The Journal of Immunology Vol. 194, No. 1 ( 2015-01-01), p. 316-324
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 194, No. 1 ( 2015-01-01), p. 316-324
    Abstract: IL-23 has been well studied in the context of T cell differentiation; however, its role in the differentiation of myeloid progenitors is less clear. In this paper, we describe a novel role of IL-23 in myeloid cell differentiation. Specifically, we have identified that in human PBMCs, IL-23 induces the expression of MDL-1, a PU.1 transcriptional target during myeloid differentiation, which orchestrates osteoclast differentiation through activation of DNAX activating protein of 12 kDa and its ITAMs. The molecular events that lead to the differentiation of human macrophages to terminally differentiated osteoclasts are dependent on spleen tyrosine kinase and phospholipase Cγ2 phosphorylation for the induction of intracellular calcium flux and the subsequent activation of master regulator osteoclast transcription factor NFATc1. IL-23–elicited osteoclastogenesis is independent of the receptor activator of NF-κB ligand pathway and uses a unique myeloid DNAX activating protein of 12 kDa–associated lectin-1+/DNAX activating protein of 12 kDa+ cell subset. Our data define a novel pathway that is used by IL-23 in myeloid cells and identify a major mechanism for the stimulation of osteoclastogenesis in inflammatory arthritis.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1401013
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2015
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Critical Role of LTB4/BLT1 in IL-23–Induced Synovial Inflammation and Osteoclastogenesis via NF-κB
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1 ( 2017-01-01), p. 452-460
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1 ( 2017-01-01), p. 452-460
    Abstract: IL-23 activates the synthesis and production of leukotriene B4 (LTB4) in myeloid cells, which modulate inflammatory arthritis. In this study we investigated the role of LTB4 and its receptor LTB4R1 (BLT1) in synovial inflammation and osteoclast differentiation. Specifically, we used IL-23 in vivo gene transfer to induce arthritis in mice and showed that elevated serum LTB4 and synovial expression of 5-lipoxygenase correlated with increased disease severity by histological evaluation and paw swelling compared with GFP gene transfer controls. To further investigate the effect of the LTB4 pathway in bone loss, we performed osteoclast differentiation assays by stimulating with M-CSF and receptor activator of NF-κB ligand bone marrow cells derived from BLT1+/+ and/or BLT1−/− mice and used quantitative PCR for gene expression analysis in terminally differentiated osteoclasts. Deficiency in BLT1 resulted in the upregulation of osteoclast-related genes and an increase in the formation of giant, multinucleated TRAP+ cells capable of F-actin ring formation. Additionally, BLT1 deficiency showed an increase of phosphorylated NF-κB and phosphorylated IκB levels in osteoclasts. We also performed real-time calcium imaging to study the effect of BLT1 deficiency in receptor activator of NF-κ-B ligand–induced activation of intracellular calcium flux in vitro. Our data show that LTB4 and its receptor BLT1 exacerbate synovial inflammation in vivo and bone resorption in vitro, suggesting that LTB4 and BLT1 could be effectively targeted for the treatment of musculoskeletal diseases.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1601346
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 5
    Online Resource
    Online Resource
    T Cell–Independent Mechanisms Associated with Neutrophil Extracellular Trap Formation and Selective Autophagy in IL-17A–Mediated Epidermal Hyperplasia
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 197, No. 11 ( 2016-12-01), p. 4403-4412
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 197, No. 11 ( 2016-12-01), p. 4403-4412
    Abstract: IL-17A has been strongly associated with epidermal hyperplasia in many cutaneous disorders. However, because IL-17A is mainly produced by αβ and γδT cells in response to IL-23, the role of T cells and IL-23 has overshadowed any IL-17A–independent actions. In this article, we report that IL-17A gene transfer induces epidermal hyperplasia in Il23r−/−Rag1−/−- and Tcrδ-deficient mice, which can be prevented by neutrophil depletion. Moreover, adoptive transfer of CD11b+Gr-1hi cells, after IL-17A gene transfer, was sufficient to phenocopy the disease. We further show that the IL-17A–induced pathology was prevented in transgenic mice with impaired neutrophil extracellular trap formation and/or neutrophils with conditional deletion of the master regulator of selective autophagy, Wdfy3. Our data demonstrate a novel T cell–independent mechanism that is associated with neutrophil extracellular trap formation and selective autophagy in IL-17A–mediated epidermal hyperplasia.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1600383
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
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