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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; Platelet-Derived Growth Factor-BB: A Stimulus for Cytokine Production by Orbital Fibroblasts in Graves' Ophthalmopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(2):1002-1007. doi: 10.1167/iovs.09-4338.
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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-κB 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.
Orbital, lung, and skin fibroblasts were stimulated with PDGF-BB, and cytokine (IL-1β, IL-6, IL-8, IL-16, CCL2, CCL5, CCL7, TNF-α) production was measured by ELISA. Involvement of NF-κB activation through PDGF signaling was investigated by electrophoretic mobility shift assay, specific NF-κB inhibitors, and the PDGF-receptor kinase inhibitor imatinib mesylate.
IL-6, IL-8, CCL2, CCL5, and CCL7 production by orbital fibroblasts was increased by PDGF-BB stimulation, whereas IL-16, IL-1β, and TNF-α production was not affected. PDGF-BB induced NF-κB activity in orbital fibroblasts, and both NF-κB 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.
PDGF-BB is a potent inducer of proinflammatory cytokines via the NF-κB 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.
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