JNK1 controls mast cell degranulation and IL-1{beta} production in inflammatory arthritis.

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.

• Authors: Monica Guma, Jun-ichi Kashiwakura, Brian Crain, Yuko Kawakami, Bruce Beutler, Gary S Firestein, Toshiaki Kawakami, Michael Karin, Maripat Corr
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 51 Pg. 22122-7 (Dec 21 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 21135226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-1beta
• Receptors, Fc
• Mitogen-Activated Protein Kinase 9
• Mitogen-Activated Protein Kinase 8
• Collagenases

Topics

• Animals
• Arthritis (genetics, immunology, metabolism, pathology)
• Bone Marrow Cells (immunology, metabolism, pathology)
• Cell Degranulation
• Collagenases (biosynthesis, genetics, immunology)
• Gene Expression Regulation (immunology)
• Humans
• Inflammation (genetics, immunology, metabolism)
• Interleukin-1beta (biosynthesis, genetics, metabolism)
• Mast Cells (immunology, metabolism, pathology)
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinase 8 (genetics, immunology, metabolism)
• Mitogen-Activated Protein Kinase 9 (genetics, immunology, metabolism)
• Receptors, Fc (genetics, immunology, metabolism)
• Signal Transduction