Gene interactions and pathways from curated databases and text-mining
Invest Ophthalmol Vis Sci 2004, PMID: 15161854

Differential involvement of phosphoinositide 3-kinase/Akt in human RPE MCP-1 and IL-8 expression.

Bian, Zong-Mei; Elner, Susan G; Yoshida, Ayako; Elner, Victor M

OBJECTIVE

To investigate the role of the phosphatidylinositol 3-kinase (PI3K) pathway and the signal mediator AP-1 in monocyte chemotactic protein (MCP)-1 and interleukin (IL)-8 gene expression in human retinal pigment epithelial (hRPE) cells.

METHODS

hRPE cells were stimulated with IL-1beta and TNF-alpha and by coculturing with monocytes in the presence or absence of a series of kinase inhibitors. The induction of MCP-1 and IL-8 protein and mRNA was determined by ELISA and RT-PCR, respectively. Western blot analysis, kinase assays, and electrophoretic mobility shift assays were used to detect the activation of signaling mediators and transcription factors.

RESULTS

Concomitant with the induction of chemokine expression by the stimuli, there was phosphorylation of PI3K and its downstream targets-namely, Akt, GSK, and FKHR. Ly294002, a specific inhibitor of PI3K, resulted in time- and dose-dependent blockade of MCP-1 mRNA expression and protein production. The IC(50) for inhibition of MCP-1 secretion induced by IL-1beta, TNF-alpha, and hRPE-monocyte binding was 16, 12, and less than 3 micro M, respectively. In contrast, Ly294002 did not inhibit the IL-8 expression induced by any of the stimuli. Ly294002 as well as U0126, SB202190, and SP600125, the selective inhibitors of MEK, p38, and JNK, respectively, strongly inhibited induced c-fos expression, whereas Ly294002 did not inhibit induction of MEK, p38, or JNK. Blockade of PI3K/Akt abolished IL-1beta-induced nuclear translocation of AP-1, whereas the induction of IkappaB degradation was unchanged.

CONCLUSIONS

The Ly294002-sensitive PI3K/Akt pathway regulates MCP-1, but not IL-8 expression in hRPE cells independent of MAPK and IkappaB. PI3K-dependent induction of hRPE c-fos and AP-1 nuclear translocation may be a target for therapies aimed at modulating MCP-1 in retinal diseases.

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Text Mining Data

MCP-1 — 3-kinase/Akt: " Differential involvement of phosphoinositide 3-kinase/Akt in human RPE MCP-1 and IL-8 expression "

(MCP)-1 ⊣ AP-1: " To investigate the role of the phosphatidylinositol 3-kinase (PI3K) pathway and the signal mediator AP-1 in monocyte chemotactic protein (MCP)-1 and interleukin (IL)-8 gene expression in human retinal pigment epithelial ( hRPE ) cells "

interleukin (IL)-8 ⊣ AP-1: " To investigate the role of the phosphatidylinositol 3-kinase (PI3K) pathway and the signal mediator AP-1 in monocyte chemotactic protein (MCP)-1 and interleukin (IL)-8 gene expression in human retinal pigment epithelial ( hRPE ) cells "

monocyte chemotactic protein (MCP)-1 ⊣ AP-1: " To investigate the role of the phosphatidylinositol 3-kinase (PI3K) pathway and the signal mediator AP-1 in monocyte chemotactic protein (MCP)-1 and interleukin (IL)-8 gene expression in human retinal pigment epithelial ( hRPE ) cells "

MCP-1 → TNF-alpha: " The IC ( 50 ) for inhibition of MCP-1 secretion induced by IL-1beta, TNF-alpha , and hRPE-monocyte binding was 16, 12, and less than 3 micro M, respectively "

MCP-1 → IL-1beta: " The IC ( 50 ) for inhibition of MCP-1 secretion induced by IL-1beta , TNF-alpha, and hRPE-monocyte binding was 16, 12, and less than 3 micro M, respectively "

AP-1 → IL-1beta: " Blockade of PI3K/Akt abolished IL-1beta induced nuclear translocation of AP-1 , whereas the induction of IkappaB degradation was unchanged "

MCP-1 — MAPK: " The Ly294002-sensitive PI3K/Akt pathway regulates MCP-1 , but not IL-8 expression in hRPE cells independent of MAPK and IkappaB "

IL-8 — MAPK: " The Ly294002-sensitive PI3K/Akt pathway regulates MCP-1, but not IL-8 expression in hRPE cells independent of MAPK and IkappaB "

AP-1 → PI3K: " PI3K dependent induction of hRPE c-fos and AP-1 nuclear translocation may be a target for therapies aimed at modulating MCP-1 in retinal diseases "

Manually curated Databases

No curated data.