title: Blocking interferon γ reduces expression of chemokines CXCL9, CXCL10 and CXCL11 and decreases macrophage infiltration in ex vivo cultured arteries from patients with giant cell arteritis.
abstract: Interferon γ (IFNγ) is considered a seminal cytokine in the pathogenesis of giant cell arteritis (GCA), but its functional role has not been investigated. We explored changes in infiltrating cells and biomarkers elicited by blocking IFNγ with a neutralising monoclonal antibody, A6, in temporal arteries from patients with GCA.
  
  
  
  Temporal arteries from 34 patients with GCA (positive histology) and 21 controls were cultured on 3D matrix (Matrigel) and exposed to A6 or recombinant IFNγ. Changes in gene/protein expression were measured by qRT-PCR/western blot or immunoassay. Changes in infiltrating cells were assessed by immunohistochemistry/immunofluorescence. Chemotaxis/adhesion assays were performed with temporal artery-derived vascular smooth muscle cells (VSMCs) and peripheral blood mononuclear cells (PBMCs).
  
  
  
  Blocking endogenous IFNγ with A6 abrogated STAT-1 phosphorylation in cultured GCA arteries. Furthermore, selective reduction in CXCL9, CXCL10 and CXCL11 chemokine expression was observed along with reduction in infiltrating CD68 macrophages. Adding IFNγ elicited consistent opposite effects. IFNγ induced CXCL9, CXCL10, CXCL11, CCL2 and intracellular adhesion molecule-1 expression by cultured VSMC, resulting in increased PBMC chemotaxis/adhesion. Spontaneous expression of chemokines was higher in VSMC isolated from GCA-involved arteries than in those obtained from controls. Incubation of IFNγ-treated control arteries with PBMC resulted in adhesion/infiltration by CD68 macrophages, which did not occur in untreated arteries.
  
  
  
  Our ex vivo system suggests that IFNγ may play an important role in the recruitment of macrophages in GCA by inducing production of specific chemokines and adhesion molecules. Vascular wall components (ie, VSMC) are mediators of these functions and may facilitate progression of inflammatory infiltrates through the vessel wall.
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Corbera-Bellalta
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Planas-Rigol
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Lozano
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Nekane
authors.initials: N
authors.lastname: Terrades-García
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Alba
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Prieto-González
authors.affiliation: Department of Emergency Medicine, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: García-Martínez
authors.affiliation: Hematopathology Section, Department of Anatomic Pathology, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Robert
authors.initials: R
authors.lastname: Albero
authors.affiliation: Genomics and Haematopathology Unit, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Enjuanes
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Georgina
authors.initials: G
authors.lastname: Espígol-Frigolé
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Hernández-Rodríguez
authors.affiliation: Division of Immunology and Allergy, University Hospital and Medical School, University of Geneva, Geneva, Switzerland.
authors.forename: Pascale
authors.initials: P
authors.lastname: Roux-Lombard
authors.affiliation: Novimmune, Geneva, Switzerland.
authors.forename: Walter G
authors.initials: WG
authors.lastname: Ferlin
authors.affiliation: Medical School, University of Geneva, Geneva, Switzerland.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dayer
authors.affiliation: Division of Immunology and Allergy, University Hospital and Medical School, University of Geneva, Geneva, Switzerland.
authors.forename: Marie H
authors.initials: MH
authors.lastname: Kosco-Vilbois
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cid
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000235:genetics / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D013700:Giant Cell Arteritis / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013699:Temporal Arteries / Q000276:immunology; D046509:Tissue Culture Techniques
chemical_list: C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma
keywords: Chemokines; Cytokines; Giant Cell Arteritis; Inflammation; Systemic vasculitis