期刊
PLOS ONE
卷 10, 期 2, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0117911
关键词
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资金
- National Science Council, Taiwan [NSC101-2321-B-182-013, NSC101-2320-B-182-039-MY3, NSC101-2314-B-182-182A-112]
- Ministry of Education, Taiwan [EMRPD1C0261, EMRPD1C0271]
- Chang Gung Medical Research Foundation, Taiwan [CMRPD1C0102, CMRPD1B0382, CMRPD1C0561, CMRPG3B1092, CMRPG3C1301]
Retinal inflammatory diseases induced by cytokines, such as tumor necrosis factor-alpha (TNF-alpha) are associated with an up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the retinal pigment epithelial cells (RPECs). Retinal pigment epithelium (RPE) is a monolayer of epithelial cells that forms the outer blood-retinal barrier in the posterior segment of the eye, and is also implicated in the pathology of, such as neovascularization in age-related macular degeneration (AMD). However, the detailed mechanisms of TNF-alpha-induced ICAM-1 expression are largely unclear in human RPECs. We demonstrated that in RPECs, TNF-alpha could induce ICAM-1 protein and mRNA expression and promoter activity, and monocyte adhesion. TNF-alpha-mediated responses were attenuated by pretreatment with the inhibitor of PKCs (Ro318220), PKC delta (Rottlerin), MEK1/2 (U0126), JNK1/2 (SP600125), or AP-1 (Tanshinone IIA) and transfection with siRNA of TNFR1, TRAF2, JNK2, p42, or c-Jun. We showed that TNF-alpha could stimulate the TNFR1 and TRAF2 complex formation. TNF-alpha stimulated JNK1/2 was also reduced by Rottlerin or SP600125. However, Rottlerin had no effect on TNF-alpha-induced p42/p44 MAPK phosphorylation. We observed that TNF-alpha induced c-Jun phosphorylation which was inhibited by Rottlerin or SP600125. On the other hand, TNF-alpha-stimulated ICAM-1 promoter activity was prominently lost in RPECs transfected with the point-mutated AP-1 ICAM-1 promoter plasmid. These results suggest that TNF-alpha-induced ICAM-1 expression and monocyte adhesion is mediated through a TNFR1/TRAF2/PKC delta/JNK1/2/c-Jun pathway in RPECs. These findings concerning TNF-alpha induced ICAM-1 expression in RPECs imply that TNF-alpha might play an important role in ocular inflammation and diseases.
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