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

Journal of Leukocyte Biology

Hitoshi Yokoyama¹  Kouji Matsushima²  Kengo Furuichi¹  Akinori Hara¹  Kazuaki Shimizu¹  Junya Yamahana¹  Shuichi Kaneko¹  Takashi Wada¹  Norihiko Sakai¹  Satoshi Kokubo¹  Toshiya Okumura¹ 

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

关键词: chemokine;    fibrosis;    TGF-β₁;    collagen I;   

DOI  :  10.1189/jlb.0305127

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Monocyte/macrophage (Mο) 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-β1 (TGF-β1), and type I collagen in circulating human CD14-positive Mo was investigated. In addition, the impact of MCP-1-specific or TGF-β1-specific antisense (AS) phosphorothioate oligodeoxynucleotides (ODN) was examined to explore the involvement of autocrine/paracrine production of MCP-1 and TGF-β1 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-β1 and a pro-α1 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-β1-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.

【 授权许可】

Unknown