JNK1 controls mast cell degranulation and IL-1{beta} production in inflammatory arthritis.
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.
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.
Monica
M
Guma
Jun-ichi
J
Kashiwakura
Brian
B
Crain
Yuko
Y
Kawakami
Bruce
B
Beutler
Gary S
GS
Firestein
Toshiaki
T
Kawakami
Michael
M
Karin
Maripat
M
Corr
D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015550:Cell Degranulation; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
D053583:Interleukin-1beta; D011961:Receptors, Fc; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D017364:Collagenases