CTGF increases IL-6 expression in human synovial fibroblasts through integrin-dependent signaling pathway

PLoS One. 2012;7(12):e51097. doi: 10.1371/journal.pone.0051097. Epub 2012 Dec 5.

Abstract

Background: Connective tissue growth factor (CTGF; also known as CCN2) is an inflammatory mediator, and shows elevated levels in regions of severe injury and inflammatory diseases. CTGF is abundantly expressed in osteoarthritis (OA). However, the relationship between CTGF and IL-6 in OA synovial fibroblasts (OASFs) is mostly unknown.

Methodology/principal findings: OASFs showed significant expression of CTGF, and expression was higher than in normal SFs. OASFs stimulation with CTGF induced concentration-dependent increases in IL-6 expression. CTGF mediated IL-6 production was attenuated by αvβ5 integrin neutralized antibody and apoptosis signal-regulating kinase 1 (ASK1) shRNA. Pretreatment with p38 inhibitor (SB203580), JNK inhibitor (SP600125), AP-1 inhibitors (Curcumin and Tanshinone IIA), and NF-κB inhibitors (PDTC and TPCK) also inhibited the potentiating action of CTGF. CTGF-mediated increase of NF-κB and AP-1 luciferase activity was inhibited by SB203580 and SP600125 or ASK1 shRNA or p38 and JNK mutant.

Conclusions/significance: Our results suggest that CTGF increased IL-6 production in OASFs via the αvβ5 integrin, ASK1, p38/JNK, and AP-1/NF-κB signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Connective Tissue Growth Factor / pharmacology*
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism*
  • Humans
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinase 5 / metabolism
  • MAP Kinase Signaling System / drug effects
  • Models, Biological
  • NF-kappa B / metabolism
  • Receptors, Vitronectin / metabolism*
  • Signal Transduction / drug effects*
  • Synovial Membrane / pathology*
  • Transcription Factor AP-1 / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • IL6 protein, human
  • Interleukin-6
  • NF-kappa B
  • Receptors, Vitronectin
  • Transcription Factor AP-1
  • integrin alphaVbeta5
  • Connective Tissue Growth Factor
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP3K5 protein, human

Grants and funding

This study was supported by grants from the National Science Council of Taiwan (NSC99-2320-B-039-003-MY3; 100-2320-B-039-028-MY3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.