The CCL2/CCR2 axis enhances vascular cell adhesion molecule-1 expression in human synovial fibroblasts

PLoS One. 2012;7(11):e49999. doi: 10.1371/journal.pone.0049999. Epub 2012 Nov 21.

Abstract

Background: Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family that is associated with the disease status and outcomes of osteoarthritis (OA). Here, we investigated the intracellular signaling pathways involved in CCL2-induced vascular cell adhesion molecule-1 (VCAM-1) expression in human OA synovial fibroblasts (OASFs).

Methodology/principal findings: Stimulation of OASFs with CCL2 induced VCAM-1 expression. CCL2-mediated VCAM-1 expression was attenuated by CCR2 inhibitor (RS102895), PKCδ inhibitor (rottlerin), p38MAPK inhibitor (SB203580), and AP-1 inhibitors (curcumin and tanshinone IIA). Stimulation of cells with CCL2 increased PKCδ and p38MAPK activation. Treatment of OASFs with CCL2 also increased the c-Jun phosphorylation and c-Jun binding to the AP-1 element on the VCAM-1 promoter. Moreover, CCL2-mediated CCR2, PKCδ, p38MAPK, and AP-1 pathway promoted the adhesion of monocytes to the OASFs monolayer.

Conclusions/significance: Our results suggest that CCL2 increases VCAM-1 expression in human OASFs via the CCR2, PKCδ, p38MAPK, c-Jun, and AP-1 signaling pathway. The CCL2-induced VCAM-1 expression promoted monocytes adhesion to human OASFs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / pharmacology
  • Benzopyrans / pharmacology
  • Cell Adhesion / drug effects
  • Chemokine CCL2* / antagonists & inhibitors
  • Chemokine CCL2* / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation / drug effects*
  • Humans
  • Imidazoles / pharmacology
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Osteoarthritis* / genetics
  • Osteoarthritis* / metabolism
  • Pyridines / pharmacology
  • Receptors, CCR2* / antagonists & inhibitors
  • Receptors, CCR2* / metabolism
  • Signal Transduction / drug effects
  • Synovial Fluid / cytology
  • Synovial Fluid / metabolism
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Transcription Factor AP-1 / metabolism
  • Vascular Cell Adhesion Molecule-1* / genetics
  • Vascular Cell Adhesion Molecule-1* / metabolism

Substances

  • Acetophenones
  • Benzopyrans
  • CCL2 protein, human
  • CCR2 protein, human
  • Chemokine CCL2
  • Imidazoles
  • Pyridines
  • Receptors, CCR2
  • Transcription Factor AP-1
  • Vascular Cell Adhesion Molecule-1
  • rottlerin
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 14
  • SB 203580

Grants and funding

This work was supported by grants from the National Science Council of Taiwan (NSC99-2320-B-039-003-MY3 and NSC100-2320-B-039-028-MY3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.