title: Cadherin-11 regulates fibroblast inflammation.
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.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sook Kyung
authors.initials: SK
authors.lastname: Chang
authors.forename: Erika H
authors.initials: EH
authors.lastname: Noss
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.forename: Zhizhan
authors.initials: Z
authors.lastname: Gu
authors.forename: Kirk
authors.initials: K
authors.lastname: Townsend
authors.forename: Rosa
authors.initials: R
authors.lastname: Grenha
authors.forename: Luis
authors.initials: L
authors.lastname: Leon
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
authors.forename: Michael B
authors.initials: MB
authors.lastname: Brenner
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental; D001172:Arthritis, Rheumatoid; D015820:Cadherins / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D053583:Interleukin-1beta; D015850:Interleukin-6; D051379:Mice; D014409:Tumor Necrosis Factor-alpha
chemical_list: D015820:Cadherins; D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C086960:osteoblast cadherin