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1 From the Departments of Ophthalmology and 2 Pathology, University of Michigan, Ann Arbor.
PURPOSE. To determine the signal mediators involved in glycated human serum albumin (GHSA) stimulation of interleukin (IL)-8 and monocyte chemotactic protein (MCP)-1 secretion in human retinal pigment epithelium (hRPE) cells.
METHODS. hRPE cells were stimulated by GHSA in the presence or absence of a series of kinase inhibitors. The induced IL-8 and MCP-1 mRNA and proteins were determined by reverse transcription–polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Western blot analysis, electrophoretic mobility shift assay, and immunohistochemical staining were used to analyze activation of signaling mediators and transcription factors.
RESULTS. Incubation of hRPE cells with GHSA resulted in rapid activation of
Raf-1, extracellular signal-regulated protein kinases (ERK) 1/2, p38,
and the transcription factor nuclear factor (NF)-
B. Coincubation of
hRPE cells with the mitogen-activated protein (MAP) kinase (MEK)
inhibitor U0126; NF-B inhibitors BAY11-7085, caffeic acid phenethyl
ester (CAPE), parthenolide, and curcumin; protein kinase (PK)C
inhibitor Ro318220; and protein tyrosine kinase (PTK) inhibitor
genistein largely eliminated most of the stimulated production of IL-8
and MCP-1. Combined inhibition of MEK by U0126, p38 by SB202190, and
Janus kinase (jak) by AG490 revealed that GHSA stimulation of IL-8
production was predominately mediated by MEK and to a lesser extent by
p38 pathways, whereas activation of MEK, p38, and jak was required for
maximal MCP-1 induction. Moreover, GHSA-stimulated IL-8 secretion was
more sensitive to U0126 (50% inhibitory concentration
[IC50] = 0.5 µM) than MCP-1 (IC50 = 10
µM).
CONCLUSIONS. GHSA stimulates hRPE IL-8 and MCP-1 production through divergent and
overlapping, but not identical, intracellular signaling cascades. GHSA
induces activation of a series of kinases including PKC, PTK, MAPK,
p38, and jak and the transcription factor NF-B. The Raf/MAPK pathway
plays an essential role in GHSA signaling.
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