Article

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

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, Division of Rheumatology,School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Proceedings of the National Academy of Sciences (impact factor: 9.68). 12/2010; 107(51):22122-7. DOI:10.1073/pnas.1016401107 pp.22122-7
Source: PubMed

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.

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Keywords

abrogates joint
 
alternative therapeutic strategies
 
c-Jun N-terminal kinase
 
cartilage destruction
 
chronic inflammatory disease
 
critical
 
Current biologic therapies
 
degranulate
 
FcγR-triggered IL-1β production
 
IL-1β
 
JNK1
 
JNK1 controls mast cell degranulation
 
key pathogenic signaling cascades
 
matrix metalloproteinase biosynthesis
 
Pharmacologic JNK inhibition
 
proinflammatory function
 
Rheumatoid arthritis
 
small molecules
 
stimulation