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Extracellular Signal-Regulated Kinase Activation Predominantly in Müller Cells of Retina with Endotoxin-Induced Uveitis

¹ From the Department of Ophthalmology, Asahikawa Medical College, Asahikawa, Japan; and the ² Department of Anatomy and Neurobiology, Osaka City University, Osaka, Japan.

PURPOSE. To evaluate the consequences of mitogen-activated protein kinase (MAPK)-mediated signaling in retinas with endotoxin-induced uveitis (EIU).

METHODS. EIU was induced with footpad inoculation of lipopolysaccharide (LPS). To identify the expression and activity of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38, Western blot analysis and immunohistochemistry (IHC) were performed using antibodies against these kinases and phosphorylated forms. To evaluate the ERK mRNA expression level, semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was performed. To identify cell species that express phosphorylated (p)-ERK, simultaneous demonstration of p-ERK and glial fibrillary acidic protein (GFAP) was performed with combined IHC and in situ hybridization. Dexamethasone (Dex) was used to reduce the LPS-induced inflammatory stimulus, and changes in p-ERK expression were evaluated by Western blot analysis after treatment.

RESULTS. Only p-ERK among the phosphorylated MAPKs increased after LPS stimulation, according to Western blot analysis. p-ERK increased after LPS injection, whereas both the Western blot and RT-PCR studies showed no apparent changes in ERK-1 and -2 expression. IHC revealed that strong p-ERK-positive staining initially appeared in the Müller cell bodies. Thereafter p-ERK immunostaining was also observed transiently in the radial processes of the Müller cells. The double-labeling study revealed that almost all Müller cells were positive for GFAP and p-ERK. Dex treatment substantially reduced expression of p-ERK, beginning 12 hours after treatment.

CONCLUSIONS. The present study suggests that LPS stimulation activates ERK in Müller cells, whereas the total amount of ERK is unchanged. Because the LPS-induced p-ERK level was reduced by Dex treatment, its expression seems to be associated with ocular inflammatory stimulus. Because the inflammatory stimulus elicited in EIU upregulated ERK activity in Müller cells, activated Müller cells may play a crucial role in protecting retinal cells from such inflammation.

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