Cadherin-11 regulates fibroblast inflammation
- 2 May 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (20), 8402-8407
- https://doi.org/10.1073/pnas.1019437108
Abstract
Fibroblasts are important participants in inflammation. Although not leukocytes, their capacity to produce cytokines, chemokines, and other inflammatory factors locally in tissues suggests that they can contribute to inflammatory diseases. For example, fibroblasts in a rheumatoid arthritis (RA) joint are a dominant source of IL-6 and RANKL in the synovium, both of which are therapeutic targets for inflammation and bone erosion. Previously, we found that fibroblasts can be targeted by mAb directed against cadherin-11 (cad-11), a mesenchymal cadherin that fibroblasts selectively express. Targeting cad-11 significantly reduced inflammation as assessed by joint swelling and clinical inflammation scores. However, the mechanism by which anti–cad-11 reduced inflammation was not known. Here, we show that cad-11 engagement induces synovial fibroblasts to secret proinflammatory cytokines including IL-6. Cad-11 engagement strongly synergized with TNF-α and IL-1β in the induction of IL-6. Importantly, cad-11 activated MAP kinases and NF-κB for IL-6 induction. IL-6 levels in ankles of inflamed joints were reduced in cad-11 mutant mice compared to wild-type mice with inflammatory arthritis. Thus, we suggest that cad-11 modulates synovial fibroblasts to evoke inflammatory factors that may contribute to the inflammatory process in RA.This publication has 49 references indexed in Scilit:
- Two-step adhesive binding by classical cadherinsNature Structural & Molecular Biology, 2010
- Structure and Biochemistry of Cadherins and CateninsCold Spring Harbor Perspectives in Biology, 2009
- Clinical value of blocking IL-6 receptorCurrent Opinion in Rheumatology, 2009
- Cytokines in the pathogenesis of rheumatoid arthritisNature Reviews Immunology, 2007
- Cadherin-11 Induces Rheumatoid Arthritis Fibroblast-Like Synoviocytes to Form Lining Layers in VitroThe American Journal of Pathology, 2006
- Inhibition of joint inflammation and destruction induced by anti-type II collagen antibody/lipopolysaccharide (LPS)-induced arthritis in mice due to deletion of macrophage migration inhibitory factor (MIF)Cytokine, 2004
- Evolving concepts of rheumatoid arthritisNature, 2003
- A Point Mutation of Tyr-759 in Interleukin 6 Family Cytokine Receptor Subunit gp130 Causes Autoimmune ArthritisThe Journal of Experimental Medicine, 2002
- A new model for rheumatoid arthritis generated by engraftment of rheumatoid synovial tissue and normal human cartilage into scid miceArthritis & Rheumatism, 1994
- CADHERINS: A MOLECULAR FAMILY IMPORTANT IN SELECTIVE CELL-CELL ADHESIONAnnual Review of Biochemistry, 1990