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

Monocyte/macrophage (M) migra- tion to sites of inflammation is a prerequisite cause of organ fibrosis. The recruitment and ac- tivation of Mo are regulated by C-C chemokines, especially monocyte chemoattractant protein-1 ((MCP-1)/CC chemokine ligand 2), which inter- acts with CC chemokine receptor 2 (CCR2). However, the mechanisms leading to fibrosis via MCP-1/CCR2 signaling in Mo remain to be inves- tigated. The effect of MCP-1 on the expression of MCP-1, CCR2, transforming growth factor-1 (TGF-1), and type I collagen in circulating hu- man CD14-positive Mo was investigated. In ad- dition, the impact of MCP-1-specific or TGF-1- specific antisense (AS) phosphorothioate oligode- oxynucleotides (ODN) was examined to explore the involvement of autocrine/paracrine produc- tion of MCP-1 and TGF- 1 by human CD14- positive Mo. Furthermore, specific CCR2 inhib- itors were applied to examine the involvement of CCR2 signaling for the promotion of a fibrogenic response. The stimulation of Mo with MCP-1 in- creased mRNA levels of TGF- 1 and a pro-1 chain of type I collagen (COL1A1) as well as protein synthesis. Similarly, the expression of MCP-1 and CCR2 was enhanced by the stimula- tion with MCP-1 in dose- and time-dependent manners. This positive loop via MCP-1 was re- duced by pretreatment with MCP-1-specific AS- ODN. It was also noted that pretreatment with TGF- 1 -specific AS-ODN partially reduced COL1A1 mRNA levels. Finally, transcripts of these molecules were suppressed by pretreat- ment with specific CCR2 inhibitors. The present study demonstrated that human peripheral CD14-positive Mo contribute directly to fibro- genesis by a MCP-1/CCR2-dependent ampli- fication loop. These data suggest that fibrogenic processes in Mo regulated by MCP-1/CCR2 may be novel, therapeutic targets for combating or- gan fibrosis. J. Leukoc. Biol. 79: 555-563; 2006.