van Steensel L, Paridaens D, Dingjan G, van Daele P, van Hagen P, Kuijpers R, van den Bosch W, Drexhage H, Hooijkaas H, Dik W
Platelet-derived growth factor-BB: a stimulus for cytokine production by orbital fibroblasts in Graves' Ophthalmopathy. [JOURNAL ARTICLE]
Invest Ophthalmol Vis Sci 2009 Sep 24.
Purpose. Graves' ophthalmopathy (GO) is characterized by infiltration of immune cells into the orbit, a process in which cytokines play a central role. Orbital fibroblasts are potent producers of cytokines upon different stimuli. Recently, we 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 pro-inflammatory cytokines by orbital fibroblasts in GO. Methods. Orbital, lung and skin fibroblasts were stimulated with PDGF-BB and cytokine production (IL-1beta, IL-6, IL-8, IL-16, CCL2, CCL5, CCL7 and TNF-alpha) was measured by ELISA. Involvement of NF-kappaB activation through PDGF-signaling was investigated by Electrophoretic Mobility Shift Assay (EMSA), 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 while 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.
Conclusion. PDGF-BB is a potent inducer of pro-inflammatory cytokines via the NF-kappaB pathway in orbital fibroblasts whereas cytokine production by fibroblasts from other anatomical 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 therapeutic target in GO.
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