title: CCL2/CCR2 augments the production of transforming growth factor-beta1, type 1 collagen and CCL2 by human CD45-/collagen 1-positive cells under high glucose concentrations.
abstract: BACKGROUND
  The migration and activation of circulating profibrotic cells including fibrocytes by the action of the chemokine/chemokine receptor system has been implicated in pathological fibrogenesis. In the present study, the involvement of collagen 1 (Col1)-producing cells, CD45-positive/collagen-1-positive (CD45(+)/Col1(+)) cells originally named as fibrocytes via CC chemokine receptor 2 (CCR2), a cognate receptor of CCL2/monocyte chemoattractant protein, was examined in diabetic conditions.
  
  
  METHODS
  Human CD45(+)/Col1(+) cells originating from the peripheral blood of healthy volunteers were incubated with high concentrations of D-glucose or D-mannitol as an osmotic control for 12, 24 or 48 h. In addition, these cells were preincubated with CCL2 under high glucose concentrations. We also examined the effects of the inhibitors of glucose transporters (GLUTs), reactive oxygen species or CCR2 on the expression of transforming growth factor beta1 (TGF-β1), pro-α1 chain of Col1 (COL1A1), and CCL2.
  
  
  RESULTS
  Stimulation of CD45(+)/Col1(+) cells with high glucose concentrations increased the mRNA and protein levels of TGF-β1 and CCL2 and those of pro-COL1A1, and this effect was mediated in part by increased osmolality. Preincubation of the cells with cytochalasin B (a GLUT inhibitor) or N-acetylcysteine (an antioxidant) blocked the stimulatory effect of high glucose concentrations on these profibrotic molecules. In addition, preincubation of the cells with CCL2 enhanced the high glucose-induced upregulation of TGF-β1, pro-COL1A1 and CCL2 and migration of the cells, and this effect was partly inhibited by treatment with CCR2 inhibitors.
  
  
  CONCLUSIONS
  These results suggest that CD45(+)/Col1(+) cells may be directly involved, in part through CCL2/CCR2 signaling, in the fibrotic process under diabetic conditions.
authors.affiliation: Department of Disease Control and Homeostasis, Kanazawa University, Kanazawa, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Hara
authors.forename: Norihiko
authors.initials: N
authors.lastname: Sakai
authors.forename: Kengo
authors.initials: K
authors.lastname: Furuichi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sakai
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takuwa
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000502:physiology; D024042:Collagen Type I / Q000096:biosynthesis*; D003571:Cytochalasin B / Q000494:pharmacology; D005355:Fibrosis / Q000209:etiology; D005947:Glucose / Q000008:administration & dosage*; D051246:Glucose Transport Proteins, Facilitative / Q000096:biosynthesis; D006801:Humans; D007668:Kidney / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*
chemical_list: D018932:Chemokine CCL2; D024042:Collagen Type I; D051246:Glucose Transport Proteins, Facilitative; D054390:Receptors, CCR2; D053773:Transforming Growth Factor beta1; D003571:Cytochalasin B; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; D005947:Glucose; D000111:Acetylcysteine
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