Preconditioning with endoplasmic reticulum stress mitigates retinal endothelial inflammation via activation of X-box binding protein 1.

Abstract

Endoplasmic reticulum (ER) stress is widely implicated in various pathological conditions such as diabetes. Previously, we reported that enhanced ER stress contributes to inflammation and vascular damage in diabetic and ischemia-induced retinopathy. However, the exact role of the signaling pathways activated by ER stress in vascular inflammation remains poorly understood. In the present study, we investigated the role of X-box binding protein 1 (XBP1) in retinal adhesion molecule expression, leukostasis, and vascular leakage. Exposure of human retinal endothelial cells to low dose ER stress inducers resulted in a robust activation of XBP1 but did not affect inflammatory gene expression. However, ER stress preconditioning almost completely abolished TNF-α-elicited NF-κB activation and adhesion molecule ICAM-1 and VCAM-1 expression. Pharmaceutical inhibition of XBP1 activation or knockdown of XBP1 by siRNA markedly attenuated the effects of preconditioning on inflammation. Moreover, loss of XBP1 led to an increase in ICAM-1 and VCAM-1 expression. Conversely, overexpression of spliced XBP1 attenuated TNF-α-induced phosphorylation of IKK, IκBα, and NF-κB p65, accompanied by decreased NF-κB activity and reduced adhesion molecule expression. Finally, in vivo studies show that activation of XBP1 by ER stress preconditioning prevents TNF-α-induced ICAM-1 and VCAM-1 expression, leukostasis, and vascular leakage in mouse retinas. These results collectively indicate a protective effect of ER stress preconditioning against retinal endothelial inflammation, which is likely through activation of XBP1-mediated unfolded protein response (UPR) and inhibition of NF-κB activation.

• Authors: Jingming Li, Joshua J Wang, Sarah X Zhang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 6 Pg. 4912-21 (Feb 11 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21138840 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Icam1 protein, mouse
• RELA protein, human
• Regulatory Factor X Transcription Factors
• Rela protein, mouse
• Transcription Factor RelA
• Transcription Factors
• Tumor Necrosis Factor-alpha
• Vascular Cell Adhesion Molecule-1
• X-Box Binding Protein 1
• XBP1 protein, human
• Xbp1 protein, mouse
• Intercellular Adhesion Molecule-1

Topics

• Animals
• Capillary Permeability (drug effects, genetics)
• Cells, Cultured
• DNA-Binding Proteins (genetics, metabolism)
• Diabetic Retinopathy (genetics, metabolism, pathology)
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum (metabolism, pathology)
• Endothelium, Vascular (metabolism, pathology)
• Gene Expression Regulation (drug effects, genetics)
• Gene Knockdown Techniques
• Humans
• Inflammation (genetics, metabolism, pathology)
• Intercellular Adhesion Molecule-1 (biosynthesis, genetics)
• Mice
• Regulatory Factor X Transcription Factors
• Retinal Vessels (metabolism, pathology)
• Transcription Factor RelA (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)
• Unfolded Protein Response
• Vascular Cell Adhesion Molecule-1 (biosynthesis, genetics)
• X-Box Binding Protein 1