Orbit-infiltrating mast cells, monocytes, and macrophages produce PDGF isoforms that orchestrate orbital fibroblast activation in Graves' ophthalmopathy

L van Steensel, D Paridaens, M van Meurs, P M van Hagen, W A van den Bosch, R W A M Kuijpers, H A Drexhage, H Hooijkaas, W A Dik

Research output: Contribution to journalArticleResearchpeer-review

Abstract

PURPOSE: Platelet-derived growth factors (PDGF) are regulators of fibroblast activity that may be involved in the pathophysiology of Graves' ophthalmopathy (GO). We unraveled the expression and origin of PDGF family members in GO orbital tissue and investigated the effect of PDGF isoforms on IL-6 and hyaluronan production and proliferation by orbital fibroblasts.

METHODS: PDGF-A, PDGF-B, PDGF-C, PDGF-D, PDGF-Rα, and PDGF-Rβ expression was determined by real-time quantitative PCR and PDGF-A and PDGF-B protein expression was determined by Western blot in orbital tissues. Orbital tissues were immunohistochemically stained for PDGF-A and PDGF-B expression, together with stainings for T cells, monocytes, B cells, macrophages, and mast cells. Effects of PDGF-AA, PDGF-AB, and PDGF-BB on orbital fibroblast proliferation and IL-6 and hyaluronan production were examined. Finally, effects of PDGF-BB- and PDGF-AA-neutralizing antibodies on IL-6 and hyaluronan production in GO whole orbital tissue cultures were tested.

RESULTS: GO orbital tissue showed increased PDGF-A and PDGF-B mRNA and protein levels. Increased numbers of PDGF-A- and PDGF-B-positive monocytes, macrophages, and mast cells were present in GO orbital tissue. PDGF-BB stimulated proliferation and hyaluronan and IL-6 production by orbital fibroblasts the most, followed by PDGF-AB and PDGF-AA. Finally, in particular imatinib mesylate and PDGF-BB-neutralizing antibodies reduced IL-6 and hyaluronan production by whole orbital tissue cultures from GO patients.

CONCLUSIONS: In GO, mast cells, monocytes, and macrophages may activate orbital fibroblasts via secretion of especially PDGF-AB and PDGF-BB. Preclinical studies with whole orbital tissue cultures show that blocking PDGF-B chain containing isoforms can be a promising treatment for GO.

Original languageEnglish
Pages (from-to)E400-8
JournalThe Journal of clinical endocrinology and metabolism
Volume97
Issue number3
DOIs
Publication statusPublished - Mar 2012

Keywords

  • Benzamides
  • Cell Proliferation/drug effects
  • Eye/drug effects
  • Fibroblasts/drug effects
  • Graves Ophthalmopathy/drug therapy
  • Humans
  • Hyaluronic Acid/biosynthesis
  • Imatinib Mesylate
  • Interleukin-6/biosynthesis
  • Macrophages/drug effects
  • Mast Cells/drug effects
  • Monocytes/drug effects
  • Piperazines/pharmacology
  • Platelet-Derived Growth Factor/biosynthesis
  • Protein Kinase Inhibitors/pharmacology
  • Pyrimidines/pharmacology

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