Platelet-Derived Growth Factor-BB: A Stimulus for Cytokine Production by Orbital Fibroblasts in Graves' Ophthalmopathy

Abstract

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.

Orbit-Infiltrating Mast Cells, Monocytes, and Macrophages Produce PDGF Isoforms that Orchestrate Orbital Fibroblast Activation in Graves' Ophthalmopathy

“…Previously imatinib mesylate was found to block PDGF-BB-induced cytokine production, hyaluronan production, and proliferation by orbital fibroblast (14,15). Moreover, imatinib mesylate reduced IL-6 and hyaluronan production in cultures of whole orbital tissue from GO patients (16).…”

“…1) (9, 10). Besides IL-6, PDGF-BB also stimulates IL-8, chemokine (C-C-motif) ligand (CCL)2, CCL5, and CCL7 production by orbital fibroblasts (15). In orbital tissue, PDGF-A and PDGF-B immunoreactivity was detected in monocytes, macrophages, and mast cells, which are well-known producers of PDGF (18,20,22).…”

“…Excessive production of hyaluronan and IL-6 by orbital fibroblasts and enhanced orbital fibroblast proliferation are key events in the pathophysiology of GO (8,14,15,17). Therefore, we examined how these processes are affected by PDGF-AA, PDGF-AB, and PDGF-BB.…”

“…To date, no detailed data are present on the involvement of the different PDGF family members in GO, although some studies suggest that PDGF may be important in GO pathophysiology (4,14,15). Therefore, we here investigated the following: 1) the expression of all PDGF family members and receptors in GO orbital tissue, 2) the contribution of different intraorbital leukocyte populations to PDGF production in GO orbital tissue, and 3) the effect of different PDGF isoforms on orbital fibroblast effector functions.…”

Platelet-Derived Growth Factor-BB Enhances Adipogenesis in Orbital Fibroblasts

“…5,6,14 Therefore, we measured IL-6 secretion by the orbital fibroblasts in the culture medium. Orbital fibroblasts cultured for 3 days in differentiation medium secreted significantly (P < 0.01) higher levels of IL-6 compared to culture in nondifferentiation medium.…”