Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease marked by bone and cartilage destruction. Current biologic therapies are beneficial in only a portion of patients; hence small molecules targeting key pathogenic signaling cascades represent alternative therapeutic strategies. Here we show that c-Jun N-terminal kinase (JNK) 1, but not JNK2, is critical for joint swelling and destruction in a serum transfer model of arthritis. The proinflammatory function of JNK1 requires bone marrow-derived cells, particularly mast cells. Without JNK1, mast cells fail to degranulate efficiently and release less IL-1β after stimulation via Fcγ receptors (FcγRs). Pharmacologic JNK inhibition effectively prevents arthritis onset and abrogates joint swelling in established disease. Hence, JNK1 controls mast cell degranulation and FcγR-triggered IL-1β production, in addition to regulating cytokine and matrix metalloproteinase biosynthesis, and is an attractive therapeutic target in inflammatory arthritis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arthritis / genetics
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Arthritis / immunology
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Arthritis / metabolism*
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Arthritis / pathology
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Bone Marrow Cells / immunology
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / pathology
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Cell Degranulation*
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Collagenases / biosynthesis
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Collagenases / genetics
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Collagenases / immunology
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Gene Expression Regulation / immunology
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Humans
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / metabolism
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Interleukin-1beta / biosynthesis*
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Mast Cells / immunology
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Mast Cells / metabolism*
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Mast Cells / pathology
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 8 / genetics
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Mitogen-Activated Protein Kinase 8 / immunology
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Mitogen-Activated Protein Kinase 8 / metabolism*
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Mitogen-Activated Protein Kinase 9 / genetics
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Mitogen-Activated Protein Kinase 9 / immunology
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Mitogen-Activated Protein Kinase 9 / metabolism
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Receptors, Fc / genetics
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Receptors, Fc / immunology
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Receptors, Fc / metabolism
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Signal Transduction*
Substances
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Interleukin-1beta
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Receptors, Fc
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Mitogen-Activated Protein Kinase 9
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Mitogen-Activated Protein Kinase 8
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Collagenases