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Published online before print January 13, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0305127

Received for publication March 5, 2005.

Accepted for publication October 19, 2005.

Article

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

Norihiko Sakai ^*, Takashi Wada ^*, Kengo Furuichi ^*, Kazuaki Shimizu ^*, Satoshi Kokubo ^*, Akinori Hara ^*, Junya Yamahana ^*, Toshiya Okumura ^*, Kouji Matsushima , Hitoshi Yokoyama ^*, and Shuichi Kaneko ^*

*Department of Gastroenterology and Nephrology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan; and Department of Molecular Preventive Medicine, the University of Tokyo, Japan

	Abstract

Monocyte/macrophage (Mo) 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-₁ (TGF-₁), and type I collagen in circulating human CD14-positive Mo was investigated. In addition, the impact of MCP-1-specific or TGF-₁-specific antisense (AS) phosphorothioate oligodeoxynucleotides (ODN) was examined to explore the involvement of autocrine/paracrine production of MCP-1 and TGF-₁ 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-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 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-₁-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.

Key Words: fibrosis • TGF-₁ • collagen I

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