Cadherin-11 regulates fibroblast inflammation.

Cadherin-11 regulates fibroblast inflammation.

MedLine Citation:	PMID: 21536877 Owner: NLM Status: MEDLINE
Abstract/OtherAbstract:	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:	Sook Kyung Chang; Erika H Noss; Mei Chen; Zhizhan Gu; Kirk Townsend; Rosa Grenha; Luis Leon; Soo Young Lee; David M Lee; Michael B Brenner
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Publication Detail:	Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-05-02
Journal Detail:	Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 108 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2011 May
Date Detail:	Created Date: 2011-05-18 Completed Date: 2011-07-26 Revised Date: 2011-11-18
Medline Journal Info:	Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States
Other Details:	Languages: eng Pagination: 8402-7 Citation Subset: IM
Affiliation:	Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:	Animals Arthritis, Experimental Arthritis, Rheumatoid Cadherins / physiology* Cells, Cultured Cytokines / secretion Fibroblasts / pathology* Humans Inflammation / pathology* Interleukin-1beta Interleukin-6 Mice Tumor Necrosis Factor-alpha
Grant Support
ID/Acronym/Agency:	P01 AI 065858/AI/NIAID NIH HHS; R01 AR 48114/AR/NIAMS NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:	0/Cadherins; 0/Cytokines; 0/Interleukin-1beta; 0/Interleukin-6; 0/Tumor Necrosis Factor-alpha; 156621-71-5/osteoblast cadherin
Comments/Corrections
Comment In:	Nat Rev Rheumatol. 2011 Jul;7(7):374 [PMID: 21691325 ]

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