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Arthritis Rheumatol. 2014 Oct;66(10):2751-61. doi: 10.1002/art.38743.

Macrophage-derived delta-like protein 1 enhances interleukin-6 and matrix metalloproteinase 3 production by fibroblast-like synoviocytes in mice with collagen-induced arthritis.

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Juntendo University School of Medicine, Tokyo, Japan, and Teikyo University School of Medicine, Tokyo, Japan.



We previously reported that blockade of the Notch ligand delta-like protein 1 (DLL-1) suppressed osteoclastogenesis and ameliorated arthritis in a mouse model of rheumatoid arthritis (RA). However, the mechanisms by which joint inflammation were suppressed have not yet been revealed. This study was undertaken to determine whether DLL-1 regulates the production of RA-related proinflammatory cytokines.


Joint cells from mice with collagen-induced arthritis (CIA) and mouse fibroblast-like synoviocytes (FLS) were cultured with or without stimuli in the presence of neutralizing antibodies against Notch ligands, and the production of proinflammatory cytokines was determined by enzyme-linked immunosorbent assay. The expression of Notch receptors and ligands on mouse joint cells was determined by flow cytometry.


The production of interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by mouse joint cells with or without stimulation was suppressed by DLL-1 blockade. DLL-1 blockade also suppressed the levels of IL-6 and matrix metalloproteinase 3 (MMP-3) in the joint fluid in a mouse model of RA. However, the production of tumor necrosis factor α and IL-1β was not suppressed by DLL-1 blockade. The production of IL-6 and MMP-3 by mouse FLS was enhanced by DLL-1 stimulation as well as Notch-2 activation. Among joint cells, DLL-1 was not expressed on mouse FLS but was expressed on macrophages.


These results suggest that the interaction of DLL-1 on mouse joint macrophages with Notch-2 on mouse FLS enhances the production of IL-6 and MMP-3. Therefore, suppression of IL-6, GM-CSF, and MMP-3 production by DLL-1 blockade might be responsible for the amelioration of arthritis in a mouse model of RA.

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