TY - JOUR
T1 - Selective Transcription Factor Blockade Reduces Human Retinal Endothelial Cell Expression of Intercellular Adhesion Molecule-1 and Leukocyte Binding
AU - Ma, Yuefang
AU - Ashander, Liam M.
AU - Appukuttan, Binoy
AU - Ryan, Feargal J.
AU - Tan, Alwin C.R.
AU - Matthews, Janet M.
AU - Michael, Michael Z.
AU - Lynn, David J.
AU - Smith, Justine R.
PY - 2023/2/2
Y1 - 2023/2/2
N2 - The interaction between leukocytes and cytokine-activated retinal endothelium is an initiating step in non-infectious uveitis involving the posterior eye, mediated by cell adhesion molecules. However, because cell adhesion molecules are required for immune surveillance, therapeutic interventions would ideally be employed indirectly. Using 28 primary human retinal endothelial cell isolates, this study sought to identify transcription factor targets for reducing levels of the key retinal endothelial cell adhesion molecule, intercellular adhesion molecule (ICAM)-1, and limiting leukocyte binding to the retinal endothelium. Five candidate transcription factors—C2CD4B, EGR3, FOSB, IRF1, and JUNB—were identified by differential expression analysis of a transcriptome generated from IL-1β- or TNF-α-stimulated human retinal endothelial cells, interpreted in the context of the published literature. Further filtering involved molecular studies: of the five candidates, C2CD4B and IRF1 consistently demonstrated extended induction in IL-1β- or TNF-α-activated retinal endothelial cells and demonstrated a significant decrease in both ICAM-1 transcript and ICAM-1 membrane-bound protein expression by cytokine-activated retinal endothelial cells following treatment with small interfering RNA. RNA interference of C2CD4B or IRF1 significantly reduced leukocyte binding in a majority of human retinal endothelial cell isolates stimulated by IL-1β or TNF-α. Our observations suggest that the transcription factors C2CD4B and IRF1 may be potential drug targets for limiting leukocyte–retinal endothelial cell interactions in non-infectious uveitis involving the posterior eye.
AB - The interaction between leukocytes and cytokine-activated retinal endothelium is an initiating step in non-infectious uveitis involving the posterior eye, mediated by cell adhesion molecules. However, because cell adhesion molecules are required for immune surveillance, therapeutic interventions would ideally be employed indirectly. Using 28 primary human retinal endothelial cell isolates, this study sought to identify transcription factor targets for reducing levels of the key retinal endothelial cell adhesion molecule, intercellular adhesion molecule (ICAM)-1, and limiting leukocyte binding to the retinal endothelium. Five candidate transcription factors—C2CD4B, EGR3, FOSB, IRF1, and JUNB—were identified by differential expression analysis of a transcriptome generated from IL-1β- or TNF-α-stimulated human retinal endothelial cells, interpreted in the context of the published literature. Further filtering involved molecular studies: of the five candidates, C2CD4B and IRF1 consistently demonstrated extended induction in IL-1β- or TNF-α-activated retinal endothelial cells and demonstrated a significant decrease in both ICAM-1 transcript and ICAM-1 membrane-bound protein expression by cytokine-activated retinal endothelial cells following treatment with small interfering RNA. RNA interference of C2CD4B or IRF1 significantly reduced leukocyte binding in a majority of human retinal endothelial cell isolates stimulated by IL-1β or TNF-α. Our observations suggest that the transcription factors C2CD4B and IRF1 may be potential drug targets for limiting leukocyte–retinal endothelial cell interactions in non-infectious uveitis involving the posterior eye.
KW - C2CD4B
KW - endothelium
KW - human
KW - IRF1
KW - leukocyte
KW - retina
KW - transcription factor
KW - uveitis
UR - http://www.scopus.com/inward/record.url?scp=85149033659&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1123684
UR - http://purl.org/au-research/grants/ARC/FT130101648
U2 - 10.3390/ijms24043304
DO - 10.3390/ijms24043304
M3 - Article
C2 - 36834715
AN - SCOPUS:85149033659
SN - 1661-6596
VL - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 4
M1 - 3304
ER -