Platelet-derived growth factor-BB: a stimulus for cytokine production by orbital fibroblasts in Graves' ophthalmopathy

Leendert van Steensel, Dion Paridaens, Gemma M Dingjan, Paul L A van Daele, P Martin van Hagen, Robert W A M Kuijpers, Willem A van den Bosch, Hemmo A Drexhage, Herbert Hooijkaas, Willem A Dik

Research output: Contribution to journalArticleResearchpeer-review


PURPOSE: Graves' ophthalmopathy (GO) is characterized by the infiltration of immune cells into the orbit, a process in which cytokines play a central role. Orbital fibroblasts are potent producers of cytokines on different stimuli. Recently, the authors showed increased expression of the PDGF-B chain in GO orbital tissue. The dimeric PDGF-BB molecule has been described to activate the NF-kappaB pathway, which is well recognized for its role in regulating cytokine production. This study was conducted to determine the role of PDGF-BB in the production of proinflammatory cytokines by orbital fibroblasts in GO.

METHODS: Orbital, lung, and skin fibroblasts were stimulated with PDGF-BB, and cytokine (IL-1beta, IL-6, IL-8, IL-16, CCL2, CCL5, CCL7, TNF-alpha) production was measured by ELISA. Involvement of NF-kappaB activation through PDGF signaling was investigated by electrophoretic mobility shift assay, specific NF-kappaB inhibitors, and the PDGF-receptor kinase inhibitor imatinib mesylate.

RESULTS: IL-6, IL-8, CCL2, CCL5, and CCL7 production by orbital fibroblasts was increased by PDGF-BB stimulation, whereas IL-16, IL-1beta, and TNF-alpha production was not affected. PDGF-BB induced NF-kappaB activity in orbital fibroblasts, and both NF-kappaB inhibitors and imatinib mesylate reduced PDGF-BB-induced cytokine production. Similar, but less vigorous, effects of PDGF-BB on cytokine production were observed in lung and skin fibroblasts.

CONCLUSIONS: PDGF-BB is a potent inducer of proinflammatory cytokines via the NF-kappaB pathway in orbital fibroblasts, whereas cytokine production by fibroblasts from other anatomic locations showed a moderate response. These data suggest a possible role for PDGF-BB in regulating orbital inflammation in GO and identify the PDGF signaling cascade as a therapeutic target in GO.

Original languageEnglish
Pages (from-to)1002-7
Number of pages6
JournalInvestigative ophthalmology & visual science
Issue number2
Publication statusPublished - Feb 2010


  • Adult
  • Aged
  • Angiogenesis Inducing Agents/pharmacology
  • Becaplermin
  • Benzamides
  • Cells, Cultured
  • Cytokines/biosynthesis
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fibroblasts/drug effects
  • Graves Ophthalmopathy/metabolism
  • Humans
  • Imatinib Mesylate
  • Lung/cytology
  • Male
  • Middle Aged
  • NF-kappa B/metabolism
  • Orbit/drug effects
  • Piperazines/pharmacology
  • Platelet-Derived Growth Factor/pharmacology
  • Protein Kinase Inhibitors/pharmacology
  • Protein-Tyrosine Kinases/antagonists & inhibitors
  • Proto-Oncogene Proteins c-sis
  • Pyrimidines/pharmacology
  • Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors
  • Skin/cytology


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