title: MCP-1/CCR2-dependent loop for fibrogenesis in human peripheral CD14-positive monocytes.
abstract: 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.
authors.affiliation: Department of Gastroenterology and Nephrology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Sakai
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
authors.forename: Kengo
authors.initials: K
authors.lastname: Furuichi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimizu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kokubo
authors.forename: Akinori
authors.initials: A
authors.lastname: Hara
authors.forename: Junya
authors.initials: J
authors.lastname: Yamahana
authors.forename: Toshiya
authors.initials: T
authors.lastname: Okumura
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D024042:Collagen Type I / Q000276:immunology / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D025461:Feedback, Physiological / Q000187:drug effects / Q000276:immunology; D005355:Fibrosis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D018950:Lipopolysaccharide Receptors; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1