Cadherin-11 regulates fibroblast inflammation

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

Research output: Contribution to journalArticle

74 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8402-8407
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number20
DOIs
StatePublished - May 17 2011
Externally publishedYes

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Fibroblasts
Inflammation
Interleukin-6
Rheumatoid Arthritis
Joints
Cytokines
Osteitis
Ankle Joint
Synovial Membrane
Cadherins
osteoblast cadherin
Interleukin-1
Chemokines
Arthritis
Leukocytes
Phosphotransferases

ASJC Scopus subject areas

  • General

Cite this

Chang, S. K., Noss, E. H., Chen, M., Gu, Z., Townsend, K., Grenha, R., ... Brenner, M. B. (2011). Cadherin-11 regulates fibroblast inflammation. Proceedings of the National Academy of Sciences of the United States of America, 108(20), 8402-8407. https://doi.org/10.1073/pnas.1019437108

Cadherin-11 regulates fibroblast inflammation. / Chang, Sook Kyung; Noss, Erika H.; Chen, Mei; Gu, Zhizhan; Townsend, Kirk; Grenha, Rosa; Leon, Luis; Lee, Soo Young; Lee, David M.; Brenner, Michael B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 20, 17.05.2011, p. 8402-8407.

Research output: Contribution to journalArticle

Chang, SK, Noss, EH, Chen, M, Gu, Z, Townsend, K, Grenha, R, Leon, L, Lee, SY, Lee, DM & Brenner, MB 2011, 'Cadherin-11 regulates fibroblast inflammation', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 20, pp. 8402-8407. https://doi.org/10.1073/pnas.1019437108
Chang, Sook Kyung ; Noss, Erika H. ; Chen, Mei ; Gu, Zhizhan ; Townsend, Kirk ; Grenha, Rosa ; Leon, Luis ; Lee, Soo Young ; Lee, David M. ; Brenner, Michael B. / Cadherin-11 regulates fibroblast inflammation. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 20. pp. 8402-8407.
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