MCP-1/CCR2-dependent loop for fibrogenesis in human peripheral CD14-positive monocytes

J Leukoc Biol. 2006 Mar;79(3):555-63. doi: 10.1189/jlb.0305127. Epub 2006 Jan 13.


Monocyte/macrophage (Momicron) migration to sites of inflammation is a prerequisite cause of organ fibrosis. The recruitment and activation of Mo are regulated by C-C chemokines, especially monocyte chemoattractant protein-1 [(MCP-1)/CC chemokine ligand 2], which interacts with CC chemokine receptor 2 (CCR2). However, the mechanisms leading to fibrosis via MCP-1/CCR2 signaling in Mo remain to be investigated. The effect of MCP-1 on the expression of MCP-1, CCR2, transforming growth factor-beta1 (TGF-beta1), and type I collagen in circulating human CD14-positive Mo was investigated. In addition, the impact of MCP-1-specific or TGF-beta1-specific antisense (AS) phosphorothioate oligodeoxynucleotides (ODN) was examined to explore the involvement of autocrine/paracrine production of MCP-1 and TGF-beta1 by human CD14-positive Mo. Furthermore, specific CCR2 inhibitors were applied to examine the involvement of CCR2 signaling for the promotion of a fibrogenic response. The stimulation of Mo with MCP-1 increased mRNA levels of TGF-beta1 and a pro-alpha1 chain of type I collagen (COL1A1) as well as protein synthesis. Similarly, the expression of MCP-1 and CCR2 was enhanced by the stimulation with MCP-1 in dose- and time-dependent manners. This positive loop via MCP-1 was reduced by pretreatment with MCP-1-specific AS-ODN. It was also noted that pretreatment with TGF-beta1-specific AS-ODN partially reduced COL1A1 mRNA levels. Finally, transcripts of these molecules were suppressed by pretreatment with specific CCR2 inhibitors. The present study demonstrated that human peripheral CD14-positive Mo contribute directly to fibrogenesis by a MCP-1/CCR2-dependent amplification loop. These data suggest that fibrogenic processes in Mo regulated by MCP-1/CCR2 may be novel, therapeutic targets for combating organ fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Chemokine CCL2 / antagonists & inhibitors
  • Chemokine CCL2 / immunology
  • Chemokine CCL2 / metabolism*
  • Chemotaxis, Leukocyte / drug effects
  • Chemotaxis, Leukocyte / immunology*
  • Collagen Type I / immunology
  • Collagen Type I / metabolism
  • Collagen Type I, alpha 1 Chain
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / immunology
  • Fibrosis / immunology
  • Fibrosis / metabolism*
  • Fibrosis / physiopathology
  • Humans
  • Lipopolysaccharide Receptors / immunology*
  • Monocytes / drug effects
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Oligodeoxyribonucleotides, Antisense
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Receptors, CCR2
  • Receptors, Chemokine / antagonists & inhibitors
  • Receptors, Chemokine / immunology
  • Receptors, Chemokine / metabolism*
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1


  • CCL2 protein, human
  • CCR2 protein, human
  • Chemokine CCL2
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Lipopolysaccharide Receptors
  • Oligodeoxyribonucleotides, Antisense
  • RNA, Messenger
  • Receptors, CCR2
  • Receptors, Chemokine
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1