Targeting Endothelial Adhesion Molecule Transcription for Treatment of Inflammatory Disease: A Proof-of-Concept Study.

ABSTRACT: Targeting the endothelial adhesion molecules that control leukocyte trafficking into a tissue has been explored as a biological therapy for inflammatory diseases. However, these molecules also participate in leukocyte migration for immune surveillance, and inhibiting the physiological level of an adhesion molecule might promote infection or malignancy. We explored the concept of targeting endothelial adhesion molecule transcription during inflammation in a human system. Intercellular adhesion molecule 1 (ICAM-1) mediates leukocyte migration across the retinal endothelium in noninfectious posterior uveitis. We observed an increase in the transcription factor, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-?B1), in parallel with ICAM-1, in human retinal endothelial cells treated with tumor necrosis factor-alpha (TNF-?), and identified putative binding sites for NF-?B1 within the ICAM-1 regulatory region. We targeted induced NF-?B1 expression in endothelial cells with small interfering (si)RNA. Knockdown of NF-?B1 significantly decreased cell surface expression of ICAM-1 protein induced by TNF-? but did not reduce constitutive ICAM-1 expression. Consistently, NF-?B1 knockdown significantly reduced leukocyte binding to cell monolayers in the presence of TNF-? but did not impact baseline binding. Findings of this proof-of-concept study indicate that induced transcription of endothelial adhesion molecules might be targeted therapeutically for inflammatory disease in humans.

SUBMITTER: Ashander LM 

PROVIDER: S-EPMC4884830 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature