Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis

Yabe, Yoshihiro; Matsumoto, Tomoko; Tsurumoto, Toshiyuki; Shindo, Hiroyuki

doi:10.1007/s00776-005-0943-3

Cited by 34 publications

(27 citation statements)

References 11 publications

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“…Recently, Notch2 signaling is reported to induce differentiation of MCs from BM progenitor cells in vitro, but MCs were not depleted in Notch2 conditional knockout mice (63). The expression level of Notch ligands is reported to be upregulated at sites of chronic inflammatory diseases (8)(9)(10)(64)(65)(66), where are frequently accompanied by the accumulation of MCs (4,11,12). These results suggest that Notch receptor-ligand interactions might be important for accumulation of MCs in inflammatory but not normal condition.…”

Section: Discussionmentioning

confidence: 99%

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A Notch Ligand, Delta-Like 1 Functions As an Adhesion Molecule for Mast Cells

Murata

Okuyama

Sakano

et al. 2010

The Journal of Immunology

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Mast cells (MCs) accumulate in chronic inflammatory sites; however, it is not clear which adhesion molecules are involved in this process. Recently, the expression of Notch ligands was reported to be upregulated in inflammatory sites. Although Notch receptors are known as signaling molecules that can activate integrins, their contributions to the adhesion of MCs have not been studied. In this study, we demonstrated that mouse MCs efficiently adhered to stromal cells forced to express a Notch ligand, Delta-like 1 (Dll1). Surprisingly, the adhesion was a consequence of direct cell–cell interaction between MCs and Dll1-expressing stromal cells rather than activation of downstream effectors of Notch receptor(s)-Dll1. The adhesion of MCs to Dll1-expressing stromal cells remained even when the cell metabolism was arrested. The recognition was blocked only by inhibition of Notch receptor(s)–Dll1 interaction by addition of soluble DLL1, or mAbs against Dll1 or Notch2. Taken together, these results indicate that Notch receptor(s) and Dll1 directly promote the adhesion of MCs to stromal cells by acting as adhesion molecules. This appreciation that Notch receptor–ligand interactions have an adhesion function will provide an important clue to molecular basis of accumulation of MCs to inflammatory sites.

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Section: Discussionmentioning

confidence: 99%

“…Recently, the expression of Notch ligands was reported to be upregulated in chronic inflammatory diseases such as rheumatoid arthritis, chronic pancreatitis, and diabetic nephropathy (8)(9)(10). These conditions are frequently accompanied by accumulation of MCs (4,11,12).…”

mentioning

confidence: 99%

A Notch Ligand, Delta-Like 1 Functions As an Adhesion Molecule for Mast Cells

Murata

Okuyama

Sakano

et al. 2010

The Journal of Immunology

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“…It has also been shown that there is a high level of expression of DLL-1, Jagged-1, Notch-1, Notch-2 and Notch-3 in the synovium of RA patients 9 41. However, the precise role of each Notch ligand in autoimmune diseases remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Notch signalling ameliorates experimental inflammatory arthritis

Park

Kim

et al. 2013

Ann Rheum Dis

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ObjectiveTo test the hypothesis that Notch signalling plays a role in the pathogenesis of rheumatoid arthritis (RA) and to determine whether pharmacological inhibition of Notch signalling with γ-secretase inhibitors can ameliorate the RA disease process in an animal model.MethodsCollagen-induced arthritis was induced in C57BL/6 or Notch antisense transgenic mice by immunisation with chicken type II collagen (CII). C57BL/6 mice were administered with different doses of inhibitors of γ-secretase, an enzyme required for Notch activation, at disease onset or after onset of symptoms. Severity of arthritis was monitored by clinical and histological scores, and in vivo non-invasive near-infrared fluorescence (NIRF) images. Micro-CT was used to confirm joint destruction. The levels of CII antibodies and cytokines in serum were determined by ELISA and bead-based cytokine assay. The expression levels of cytokines were studied by quantitative PCR in rheumatoid synovial fibroblasts.ResultsThe data show that Notch signalling stimulates synoviocytes and accelerates their production of proinflammatory cytokines and immune responses involving the upregulation of IgG1 and IgG2a. Pharmacological inhibition of γ-secretase and antisense-mediated knockdown of Notch attenuates the severity of inflammatory arthritis, including arthritis indices, paw thickness, tissue damage and neutrophil infiltration, and reduces the levels of active NF-κB, ICAM-1, proinflammatory cytokines and matrix metalloproteinase-3 activity in the mouse model of RA.ConclusionsThese results suggest that Notch is involved in the pathogenesis of RA and that inhibition of Notch signalling is a novel approach for treating RA.

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“…Ishii et al and Yabe et al showed that the expression pattern of Notch homologues among synovium from OA and RA patients differed from that of normal subjects [7, 8]. Another report demonstrated the expression of Notch-1 in synoviocytes and the presence of Notch-1 fragment in the nuclei of RA synoviocytes and suggested the involvement of Notch-1 signaling in the TNF- α -induced proliferation of RA synoviocytes [9].…”

Section: Introductionmentioning

confidence: 99%

Notch Signaling Mediates TNF-α-Induced IL-6 Production in Cultured Fibroblast-Like Synoviocytes from Rheumatoid Arthritis

Jiao

Wang

et al. 2012

Clinical and Developmental Immunology

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It has been reported that Notch family proteins are expressed in synovium tissue and involved in the proliferation of synoviocyte from rheumatoid arthritis (RA). The aim of this paper was to investigate whether Notch signaling mediated TNF-α-induced cytokine production of cultured fibroblast-like synoviocytes (FLSs) from RA. Exposure of RA FLSs to TNF-α (10 ng/ml) led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels. Blockage of Notch signaling by a γ-secretase inhibitor (DAPT) inhibited IL-6 secretion of RA FLSs in response to TNF-α while treatment with recombinant fusion protein of Notch ligand Delta-like 1 promoted such response. TNF-α stimulation also induced IL-6 secretion in OA FLSs; however, the Hes-1 level remained unaffected. Our data confirm the functional involvement of Notch pathway in the pathophysiology of RA FLSs which may provide a new target for RA therapy.

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Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis

Cited by 34 publications

References 11 publications

A Notch Ligand, Delta-Like 1 Functions As an Adhesion Molecule for Mast Cells

A Notch Ligand, Delta-Like 1 Functions As an Adhesion Molecule for Mast Cells

Inhibition of Notch signalling ameliorates experimental inflammatory arthritis

Notch Signaling Mediates TNF-α-Induced IL-6 Production in Cultured Fibroblast-Like Synoviocytes from Rheumatoid Arthritis

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