title: The CC chemokine eotaxin/CCL11 has a selective profibrogenic effect on human lung fibroblasts.
abstract: BACKGROUND
  Eotaxin/CCL11 plays an important role in asthma. It acts through the chemokine receptor CCR3 expressed on hematopoietic and nonhematopoietic cells in the lung.
  
  
  OBJECTIVE
  To determine whether eotaxin/CCL11 modulates lung and bronchial fibroblast properties and thereby might contribute to airway remodeling.
  
  
  METHODS
  CCR3 expression was characterized on a lung fibroblast line (MRC-5; flow cytometry, fluorescent microscopy, RT-PCR, and Northern blotting), on primary bronchial fibroblasts (flow cytometry), and on fibroblasts in human lung tissue (confocal laser microscopy). The effects of eotaxin/CCL11 on lung fibroblast migration (Boyden chamber), proliferation (tritiated thymidine incorporation), alpha-smooth muscle actin expression (ELISA), 3-dimensional collagen gel contraction (floating gel), pro-alpha1(I) collagen mRNA (Northern blotting), total collagen synthesis (tritiated proline incorporation), matrix metalloproteinase activity (gelatin zymography), and TGF-beta(1) release (ELISA) were evaluated. The contribution of eotaxin/CCL11/CCR3 binding on lung fibroblasts was also investigated by neutralizing experiments.
  
  
  RESULTS
  CCR3 is constitutively expressed in cultured lung and primary bronchial fibroblasts and colocalizes with specific surface markers for human fibroblasts in lung tissue. Eotaxin/CCL11 selectively modulates fibroblast activities by increasing their proliferation, matrix metalloproteinase 2 activity, and collagen synthesis but not their differentiation into myofibroblasts, contractility in collagen gel, or TGF-beta(1) release. Eotaxin/CCL11 enhances migration of lung fibroblasts in response to nonspecific chemoattractants, and this effect is completely inhibited by anti-CCR3-neutralizing antibodies.
  
  
  CONCLUSIONS
  These data demonstrate that eotaxin/CCL11 has a direct and selective profibrogenic effect on lung and bronchial fibroblasts, providing a novel mechanism whereby eotaxin/CCL11 can participate in airway remodeling in asthma.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Puxeddu
authors.forename: Reem
authors.initials: R
authors.lastname: Bader
authors.forename: Adrian Martin
authors.initials: AM
authors.lastname: Piliponsky
authors.forename: Reuven
authors.initials: R
authors.lastname: Reich
authors.forename: Francesca
authors.initials: F
authors.lastname: Levi-Schaffer
authors.forename: Neville
authors.initials: N
authors.lastname: Berkman
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000502:physiology*; D002633:Chemotaxis; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008875:Middle Aged; D011498:Protein Precursors / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000209:etiology*; D012333:RNA, Messenger / Q000032:analysis; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000032:analysis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
chemical_list: C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D011498:Protein Precursors; D012333:RNA, Messenger; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D020778:Matrix Metalloproteinase 2