title: Endoplasmic reticulum-resident chaperones modulate the inflammatory and angiogenic responses of endothelial cells.
abstract: BACKGROUND
  Wound healing depends on a well-balanced regulation of inflammation and angiogenesis. In chronic wounds the healing process is disturbed and inflammation persists. Regulation of wound closure is controlled by transmembrane and extracellular proteins, the folding and maturation of which occur in the endoplasmic reticulum (ER) by ER-resident chaperone machinery.
  
  
  OBJECTIVE
  To study the role of the ER-resident chaperones BiP/Grp78, its cochaperone Mdg1/ERdJ4, and Grp94 in chronic, nonhealing wounds.
  
  
  METHODS
  Immunohistochemical staining of these chaperones in individual human biopsies and investigation of the possible role of BiP and Mdg1 in endothelial cells, focusing on their inflammatory response and angiogenic potential.
  
  
  RESULTS
  In all chronic wounds investigated, the levels of these ER-resident chaperones were elevated in endothelial cells and leucocytes. The proangiogenic role of BiP has been shown in tumour growth studies before and was confirmed in this study. Proangiogenic activity of the cochaperone Mdg1 has been postulated before but could not be confirmed in this study. The chemokine tumour necrosis factor (TNF)-α was shown to trigger the presentation of proinflammatory adhesion molecules and the release of proinflammatory cytokines. Here we show that TNF-α does not affect endogenous chaperone levels, but that the ER-resident chaperones BiP and Mdg1 modulate the cellular TNF-α-induced proinflammatory response.
  
  
  CONCLUSIONS
  According to the presented data we assume that in chronic wounds upregulated levels of ER-resident chaperones might contribute to persistent inflammation in chronic wounds. Therapies to downregulate chaperone levels might provide a tool that switches the imbalanced chronic wound microenvironment from inflammation to healing.
authors.affiliation: Institute of Pathology, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131, Mainz, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Tsaryk
authors.affiliation: Department of Rheumatology and Clinical Immunology, Medical University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.
authors.forename: N M
authors.initials: NM
authors.lastname: Bartholomä
authors.affiliation: Zentrum für Pathologie Essen-Mitte, Am Deimelsberg 34a, 45276, Essen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Simiantonaki
authors.affiliation: Institute of Pathology, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131, Mainz, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Anspach
authors.affiliation: Department of Cell Biology, Rostock University Medical Center, Schillingallee 69, 18057, Rostock, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Peters
authors.affiliation: Department of Cardiovascular Surgery, Heart Center, University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Heilmann
authors.affiliation: Institute of Pathology, University Medical Center, Johannes Gutenberg University, Langenbeckstraße 1, 55131, Mainz, Germany.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kirkpatrick
authors.affiliation: Institute of Anatomy II, Medical University of Cologne, Joseph-Stelzmann-Straße 9, 50931, Cologne, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Pröls
mesh_terms: D002478:Cells, Cultured; D002908:Chronic Disease; D015536:Down-Regulation / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000502:physiology; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D018832:Molecular Chaperones / Q000378:metabolism / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*
chemical_list: C478021:DNAJB9 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D050956:HSP40 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D014409:Tumor Necrosis Factor-alpha; C053387:endoplasmin