title: Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis.
abstract: OBJECTIVE
  Lymphatic endothelial dysfunction underlies the pathogenesis of many chronic inflammatory disorders. The proinflammatory cytokine tumor necrosis factor (TNF) is known for its role in disrupting the function of the lymphatic vasculature. This study investigates the ability of apolipoprotein (apo) A-I, the principal apolipoprotein of high-density lipoproteins, to preserve the normal function of lymphatic endothelial cells treated with TNF.
  
  
  RESULTS
  TNF decreased the ability of lymphatic endothelial cells to form tube-like structures. Preincubation of lymphatic endothelial cells with apoA-I attenuated the TNF-mediated inhibition of tube formation in a concentration-dependent manner. In addition, apoA-I reversed the TNF-mediated suppression of lymphatic endothelial cell migration and lymphatic outgrowth in thoracic duct rings. ApoA-I also abrogated the negative effect of TNF on lymphatic neovascularization in an ATP-binding cassette transporter A1-dependent manner. At the molecular level, this involved downregulation of TNF receptor-1 and the conservation of prospero-related homeobox gene-1 expression, a master regulator of lymphangiogenesis. ApoA-I also re-established the normal phenotype of the lymphatic network in the diaphragms of human TNF transgenic mice.
  
  
  CONCLUSIONS
  ApoA-I restores the neovascularization capacity of the lymphatic system during TNF-mediated inflammation. This study provides a proof-of-concept that high-density lipoprotein-based therapeutic strategies may attenuate chronic inflammation via its action on lymphatic vasculature.
authors.affiliation: From the Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Immune Imaging, Centenary Institute, Newtown, New South Wales, Australia (R.B., A.C., W.W.); Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Clinical Immunology and Rheumatology, Academic Medical Centre, Amsterdam, the Netherlands (P.P.T.); GlaxoSmithKline, Stevenage, United Kingdom (P.P.T.); Department of Rheumatology, Ghent University, Ghent, Belgium (P.P.T.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (A.C., P.J.B., K.A.R.); Discipline of Dermatology, Sydney Medical School, Sydney, New South Wales, Australia (W.W.); and Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (W.W.).
authors.forename: Radjesh
authors.initials: R
authors.lastname: Bisoendial
authors.affiliation: From the Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Immune Imaging, Centenary Institute, Newtown, New South Wales, Australia (R.B., A.C., W.W.); Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Clinical Immunology and Rheumatology, Academic Medical Centre, Amsterdam, the Netherlands (P.P.T.); GlaxoSmithKline, Stevenage, United Kingdom (P.P.T.); Department of Rheumatology, Ghent University, Ghent, Belgium (P.P.T.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (A.C., P.J.B., K.A.R.); Discipline of Dermatology, Sydney Medical School, Sydney, New South Wales, Australia (W.W.); and Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (W.W.).
authors.forename: Fatiha
authors.initials: F
authors.lastname: Tabet
authors.affiliation: From the Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Immune Imaging, Centenary Institute, Newtown, New South Wales, Australia (R.B., A.C., W.W.); Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Clinical Immunology and Rheumatology, Academic Medical Centre, Amsterdam, the Netherlands (P.P.T.); GlaxoSmithKline, Stevenage, United Kingdom (P.P.T.); Department of Rheumatology, Ghent University, Ghent, Belgium (P.P.T.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (A.C., P.J.B., K.A.R.); Discipline of Dermatology, Sydney Medical School, Sydney, New South Wales, Australia (W.W.); and Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (W.W.).
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.affiliation: From the Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Immune Imaging, Centenary Institute, Newtown, New South Wales, Australia (R.B., A.C., W.W.); Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Clinical Immunology and Rheumatology, Academic Medical Centre, Amsterdam, the Netherlands (P.P.T.); GlaxoSmithKline, Stevenage, United Kingdom (P.P.T.); Department of Rheumatology, Ghent University, Ghent, Belgium (P.P.T.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (A.C., P.J.B., K.A.R.); Discipline of Dermatology, Sydney Medical School, Sydney, New South Wales, Australia (W.W.); and Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (W.W.).
authors.forename: Francine
authors.initials: F
authors.lastname: Petrides
authors.affiliation: From the Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Immune Imaging, Centenary Institute, Newtown, New South Wales, Australia (R.B., A.C., W.W.); Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Clinical Immunology and Rheumatology, Academic Medical Centre, Amsterdam, the Netherlands (P.P.T.); GlaxoSmithKline, Stevenage, United Kingdom (P.P.T.); Department of Rheumatology, Ghent University, Ghent, Belgium (P.P.T.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (A.C., P.J.B., K.A.R.); Discipline of Dermatology, Sydney Medical School, Sydney, New South Wales, Australia (W.W.); and Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (W.W.).
authors.forename: Luisa F
authors.initials: LF
authors.lastname: Cuesta Torres
authors.affiliation: From the Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Immune Imaging, Centenary Institute, Newtown, New South Wales, Australia (R.B., A.C., W.W.); Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Clinical Immunology and Rheumatology, Academic Medical Centre, Amsterdam, the Netherlands (P.P.T.); GlaxoSmithKline, Stevenage, United Kingdom (P.P.T.); Department of Rheumatology, Ghent University, Ghent, Belgium (P.P.T.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (A.C., P.J.B., K.A.R.); Discipline of Dermatology, Sydney Medical School, Sydney, New South Wales, Australia (W.W.); and Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (W.W.).
authors.forename: Liming
authors.initials: L
authors.lastname: Hou
authors.affiliation: From the Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Immune Imaging, Centenary Institute, Newtown, New South Wales, Australia (R.B., A.C., W.W.); Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Clinical Immunology and Rheumatology, Academic Medical Centre, Amsterdam, the Netherlands (P.P.T.); GlaxoSmithKline, Stevenage, United Kingdom (P.P.T.); Department of Rheumatology, Ghent University, Ghent, Belgium (P.P.T.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (A.C., P.J.B., K.A.R.); Discipline of Dermatology, Sydney Medical School, Sydney, New South Wales, Australia (W.W.); and Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (W.W.).
authors.forename: Adam
authors.initials: A
authors.lastname: Cook
authors.affiliation: From the Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Immune Imaging, Centenary Institute, Newtown, New South Wales, Australia (R.B., A.C., W.W.); Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Clinical Immunology and Rheumatology, Academic Medical Centre, Amsterdam, the Netherlands (P.P.T.); GlaxoSmithKline, Stevenage, United Kingdom (P.P.T.); Department of Rheumatology, Ghent University, Ghent, Belgium (P.P.T.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (A.C., P.J.B., K.A.R.); Discipline of Dermatology, Sydney Medical School, Sydney, New South Wales, Australia (W.W.); and Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (W.W.).
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Barter
authors.affiliation: From the Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Immune Imaging, Centenary Institute, Newtown, New South Wales, Australia (R.B., A.C., W.W.); Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Clinical Immunology and Rheumatology, Academic Medical Centre, Amsterdam, the Netherlands (P.P.T.); GlaxoSmithKline, Stevenage, United Kingdom (P.P.T.); Department of Rheumatology, Ghent University, Ghent, Belgium (P.P.T.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (A.C., P.J.B., K.A.R.); Discipline of Dermatology, Sydney Medical School, Sydney, New South Wales, Australia (W.W.); and Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (W.W.).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
authors.affiliation: From the Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Immune Imaging, Centenary Institute, Newtown, New South Wales, Australia (R.B., A.C., W.W.); Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (R.B., F.T., F.P., L.F.C.T., L.H., P.J.B., K.A.R.); Department of Clinical Immunology and Rheumatology, Academic Medical Centre, Amsterdam, the Netherlands (P.P.T.); GlaxoSmithKline, Stevenage, United Kingdom (P.P.T.); Department of Rheumatology, Ghent University, Ghent, Belgium (P.P.T.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (A.C., P.J.B., K.A.R.); Discipline of Dermatology, Sydney Medical School, Sydney, New South Wales, Australia (W.W.); and Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (W.W.). k.rye@unsw.edu.au.
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D042583:Lymphangiogenesis / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D013897:Thoracic Duct / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D018398:Homeodomain Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; C577833:Abca1 protein, mouse; C505693:APOA1 protein, human; C506236:Tnfrsf1a protein, mouse
keywords: apolipoprotein A-I; inflammation; lymphangiogenesis; lymphatic system; receptors; tumor necrosis factor