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1 From the Departments of Pathology and 2 Ophthalmology, Keck School of Medicine at the University of Southern California; and 3 Doheny Eye Institute, Los Angeles, California.
PURPOSE. Adhesion and migration of retinal pigment epithelial (RPE) cells to
provisional extracellular matrices (ECM) is important in the
development of epiretinal membranes found in proliferative
vitreoretinopathy (PVR). Tumor necrosis factor alpha (TNF-
) is found
in PVR membranes and regulates many functions of RPE cells. In this
study, the effects of TNF- on adhesion and migration of RPE cells to
various components of ECM were examined and elucidation of the
mechanism of the response was attempted.
METHODS. Mitogen activated protein kinase (ERK1/2; MAPK) activation was measured
by immunoblot. RPE cells pretreated with TNF- (10 ng/ml) or TNF-
+ PD98059 (a specific inhibitor of MAPK, 30 µM) for 24 hours were
compared with control RPE. Attachment was measured by modified MTT
assay on fibronectin and collagen types I and IV. Spreading was
measured by staining with fluo3-AM and confocal laser scanning
microscopy. Migration of RPE cells on substrates was determined by
Boyden chamber assay using PDGF-BB (20 ng/ml) as a chemotactic factor.
Integrin expression was determined by flow cytometry and RT-PCR.
RESULTS. TNF- rapidly activated MAPK and increased the extent of attachment,
spreading and migration on fibronectin and collagen type I
(P < 0.01) but not on collagen type IV. TNF-stimulated
RPE cells showed increased mRNA and surface protein expression for 1
and 5 integrin (P < 0.01) but not 3 integrin
subunit. Neutralizing the anti-1 antibody inhibited migration on
collagen type I, whereas 5 antibody inhibited fibronectin-induced
migration. Treatment with both TNF and PD98095 reduced attachment and
migration on provisional ECM and reduced the upregulated integrin
expression to control levels.
CONCLUSIONS. After treatment with TNF-, there is increased expression of specific
integrins associated with increased adhesion and migration on
provisional ECM (fibronectin and collagen type I). This effect is
mediated, at least in part, by activation of MAPK signaling
pathway.
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