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

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Chiyoko Sekine, Toshihiro Nanki, Hideo Yagita
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 66 Issue 10 Pg. 2751-61 (Oct 2014) ISSN: 2326-5205 [Electronic] United States
• PMID: 24943093 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by the American College of Rheumatology.

Chemical References

• Calcium-Binding Proteins
• Dlk1 protein, mouse
• Intercellular Signaling Peptides and Proteins
• Interleukin-6
• Granulocyte-Macrophage Colony-Stimulating Factor
• Matrix Metalloproteinase 3

Topics

• Animals
• Arthritis, Experimental (metabolism)
• Arthritis, Rheumatoid (metabolism)
• Calcium-Binding Proteins
• Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Interleukin-6 (metabolism)
• Joints (metabolism)
• Male
• Matrix Metalloproteinase 3 (metabolism)
• Mice
• Mice, Inbred DBA
• Synovial Fluid (metabolism)
• Synovial Membrane (metabolism)