JNK1 controls mast cell degranulation and IL-1β production in inflammatory arthritis

M Guma, J Kashiwakura, B Crain… - Proceedings of the …, 2010 - National Acad Sciences
M Guma, J Kashiwakura, B Crain, Y Kawakami, B Beutler, GS Firestein, T Kawakami…
Proceedings of the National Academy of Sciences, 2010National Acad Sciences
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 …
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.
National Acad Sciences