TNF-α mediates PKCδ/JNK1/2/c-Jun-dependent monocyte adhesion via ICAM-1 induction in human retinal pigment epithelial cells.

Abstract

Retinal inflammatory diseases induced by cytokines, such as tumor necrosis factor-α (TNF-α) 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-α-induced ICAM-1 expression are largely unclear in human RPECs. We demonstrated that in RPECs, TNF-α could induce ICAM-1 protein and mRNA expression and promoter activity, and monocyte adhesion. TNF-α-mediated responses were attenuated by pretreatment with the inhibitor of PKCs (Ro318220), PKCδ (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-α could stimulate the TNFR1 and TRAF2 complex formation. TNF-α-stimulated JNK1/2 was also reduced by Rottlerin or SP600125. However, Rottlerin had no effect on TNF-α-induced p42/p44 MAPK phosphorylation. We observed that TNF-α induced c-Jun phosphorylation which was inhibited by Rottlerin or SP600125. On the other hand, TNF-α-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-α-induced ICAM-1 expression and monocyte adhesion is mediated through a TNFR1/TRAF2/PKCδ/JNK1/2/c-Jun pathway in RPECs. These findings concerning TNF-α-induced ICAM-1 expression in RPECs imply that TNF-α might play an important role in ocular inflammation and diseases.

• Authors: I-Ta Lee, Shiau-Wen Liu, Pei-Ling Chi, Chih-Chung Lin, Li-Der Hsiao, Chuen-Mao Yang
• Journal: PloS one (PLoS One) Vol. 10 Issue 2 Pg. e0117911 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25675437 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-jun
• Receptors, Tumor Necrosis Factor, Type I
• Retinal Pigments
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1
• Mitogen-Activated Protein Kinase 9
• Protein Kinase C-delta
• Mitogen-Activated Protein Kinase 8

Topics

• Cell Adhesion (drug effects, genetics)
• Cell Line
• Epithelial Cells (metabolism)
• Gene Expression
• Humans
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 8 (metabolism)
• Mitogen-Activated Protein Kinase 9 (metabolism)
• Monocytes (drug effects, metabolism)
• Protein Kinase C-delta (metabolism)
• Proto-Oncogene Proteins c-jun (metabolism)
• Receptors, Tumor Necrosis Factor, Type I (metabolism)
• Retinal Pigments (metabolism)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism, pharmacology)