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

Academic Article
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Overview

authors

  • Guma, M.
  • Kashiwakura, J.
  • Crain, B.
  • Kawakami, Y.
  • Beutler, Bruce
  • Firestein, G. S.
  • Kawakami, T.
  • Karin, M.
  • Corr, M.

publication date

  • December 2010

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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-1? after stimulation via Fc? receptors (Fc?Rs). Pharmacologic JNK inhibition effectively prevents arthritis onset and abrogates joint swelling in established disease. Hence, JNK1 controls mast cell degranulation and Fc?R-triggered IL-1? production, in addition to regulating cytokine and matrix metalloproteinase biosynthesis, and is an attractive therapeutic target 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.

subject areas

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

keywords

  • Fc gamma receptor
  • immune complex
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Identity

PubMed Central ID

  • PMC3009768

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1016401107

PubMed ID

  • 21135226
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Additional Document Info

start page

  • 22122

end page

  • 22127

volume

  • 107

issue

  • 51

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