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-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. Methods. 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. Results. 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. Conclusions. 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.

dx.doi.org/10.1167/iovs.09-4338, hdl.handle.net/1765/69251
Investigative Ophthalmology & Visual Science
Department of Ophthalmology

van Steensel, L, Paridaens, A.D.A, Dingjan, G.M, van Daele, P.L.A, van Hagen, P.M, Kuijpers, R.W.A.M, … Dik, W.A. (2010). Platelet-derived growth factor-BB: A stimulus for cytokine production by orbital fibroblasts in graves' ophthalmopathy. Investigative Ophthalmology & Visual Science, 51(2), 1002–1007. doi:10.1167/iovs.09-4338