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Regulation of interleukin-1β–induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts

  1. Salahuddin Ahmed1,*,
  2. Angela Pakozdi1,
  3. Alisa E. Koch2

Article first published online: 25 JUL 2006

DOI: 10.1002/art.22023

Issue

Arthritis & Rheumatism

Arthritis & Rheumatism

Volume 54, Issue 8, pages 2393–2401, August 2006

Additional Information

How to Cite

Ahmed, S., Pakozdi, A. and Koch, A. E. (2006), Regulation of interleukin-1β–induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts. Arthritis & Rheumatism, 54: 2393–2401. doi: 10.1002/art.22023

Author Information

  1. 1

    University of Michigan Medical School, Ann Arbor

  2. 2

    VA Medical Center and University of Michigan Medical School, Ann Arbor, Michigan

*Department of Internal Medicine/Division of Rheumatology, University of Michigan Medical School, BSRB Room 4388, 109 Zina Pitcher Drive, Ann Arbor, MI 48109-2200

Publication History

  1. Issue published online: 25 JUL 2006
  2. Article first published online: 25 JUL 2006
  3. Manuscript Accepted: 8 MAY 2006
  4. Manuscript Received: 23 DEC 2005

Funded by

  • NIH. Grant Numbers: AI-40987, AR-48267
  • Frederick G. L. Huetwell and William D. Robinson, MD, Professorship in Rheumatology
  • Office of Research and Development, Medical Research Service, Department of Veterans Affairs

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Abstract

Objective

To evaluate the efficacy of epigallocatechin-3-gallate (EGCG), a potent antiinflammatory molecule, in regulating interleukin-1β (IL-1β)–induced production of the chemokines RANTES (CCL5), monocyte chemoattractant protein 1 (MCP-1/CCL2), epithelial neutrophil–activating peptide 78 (ENA-78/CXCL5), growth-regulated oncogene α (GROα/CXCL1), and matrix metalloproteinase 2 (MMP-2) activity in rheumatoid arthritis (RA) synovial fibroblasts.

Methods

Fibroblasts obtained from RA synovium were grown, and conditioned medium was obtained. Cell viability was determined by MTT assay. RANTES, MCP-1, ENA-78, and GROα produced in culture supernatants were measured by enzyme-linked immunosorbent assay. MMP-2 activity was analyzed by gelatin zymography. Western blotting was used to study the phosphorylation of protein kinase C (PKC) isoforms and nuclear translocation of NF-κB.

Results

EGCG was nontoxic to RA synovial fibroblasts. Treatment with EGCG at 10 μM or 20 μM significantly inhibited IL-1β–induced ENA-78, RANTES, and GROα, but not MCP-1 production in a concentration-dependent manner. EGCG at 50 μM caused a complete block of IL-1β–induced production of RANTES, ENA-78, and GROα, and reduced production of MCP-1 by 48% (P < 0.05). Zymography showed that EGCG blocked constitutive, IL-1β–induced, and chemokine-mediated MMP-2 activity. Evaluation of signaling events revealed that EGCG preferentially blocked the phosphorylation of PKCδ and inhibited the activation and nuclear translocation of NF-κB in IL-1β–treated RA synovial fibroblasts.

Conclusion

These results suggest that EGCG may be of potential therapeutic value in inhibiting joint destruction in RA.

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