Platelet-derived growth factor-BB: a stimulus for cytokine production by orbital fibroblasts in Graves' ophthalmopathy.
OBJECTIVE
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.
van Steensel
Leendert
L
Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Paridaens
Dion
D
Dingjan
Gemma M
GM
van Daele
Paul L A
PL
van Hagen
P Martin
PM
Kuijpers
Robert W A M
RW
van den Bosch
Willem A
WA
Drexhage
Hemmo A
HA
Hooijkaas
Herbert
H
Dik
Willem A
WA
D000328:Adult; D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000077214:Becaplermin; D001549:Benzamides; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D049970:Graves Ophthalmopathy / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D008168:Lung / Q000166:cytology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009915:Orbit / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000494:pharmacology; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D012867:Skin / Q000166:cytology
D043925:Angiogenesis Inducing Agents; D001549:Benzamides; D016207:Cytokines; D016328:NF-kappa B; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000077214:Becaplermin; D000068877:Imatinib Mesylate; C099852:PDGF receptor tyrosine kinase; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor