Role of IL-6 in angiotensin II-induced retinal vascular inflammation.
OBJECTIVE
The production of proinflammatory cytokines has been shown to play a critical role in a variety of retinal vascular diseases. Angiotensin II and VEGF have been implicated in the initiation of vascular inflammation and retinal vascular disease. However, detailed mechanisms of this process and interactions between inflammatory agonists and angiotensin II in promoting retinopathy are poorly understood. The present study was an investigation of the role of interleukin (IL)-6 in angiotensin II-induced retinopathy.


METHODS
Rats and IL-6-deficient and wild-type mice were treated with angiotensin II or IL-6, and their retinas were analyzed for leukocyte adhesion or for the expression and localization of VEGF or IL-6. Leukocyte adhesion was assayed by concanavalin A labeling. Vascular density was determined by morphometric analysis. NADPH oxidase activity was assayed by dihydroethidium imaging of superoxide.


RESULTS
Intravitreal injection of angiotensin II caused increases in IL-6 mRNA and protein and in leukocyte adhesion to the retinal vessels. IL-6 protein was localized to CD11b-positive microglia and macrophage-like cells. Angiotensin II treatment stimulated increases in retinal levels of VEGF expression and NADPH oxidase activity, which were associated with increased surface area and remodeling of the retinal vessels. These effects were blocked by knocking out IL-6. Intravitreal IL-6 directly induced leukocyte adhesion in both wild-type and IL-6-deficient mice.


CONCLUSIONS
The results indicate that IL-6 expression is essential for angiotensin II-induced increases in retinal VEGF expression, leukostasis, and vascular remodeling. The data suggest a critical role for IL-6 in mediating angiotensin II-induced retinal vascular inflammation and remodeling.
Rojas
Modesto
M
VA Medical Center, Augusta, Georgia, USA.
Zhang
Wenbo
W
Lee
Dexter L
DL
Romero
Maritza J
MJ
Nguyen
Doan T
DT
Al-Shabrawey
Mohamed
M
Tsai
Nai-Tse
NT
Liou
Gregory I
GI
Brands
Michael W
MW
Caldwell
Robert W
RW
Caldwell
Ruth B
RB
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D004797:Enzyme-Linked Immunosorbent Assay; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D007962:Leukocytes / Q000378:metabolism; D018921:Leukostasis / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D019255:NADPH Oxidases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D031300:Retinal Vasculitis / Q000139:chemically induced / Q000378:metabolism*; D012171:Retinal Vessels / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D015850:Interleukin-6; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D014662:Vasoconstrictor Agents; C467480:vascular endothelial growth factor A, mouse; C467498:vascular endothelial growth factor A, rat; D013481:Superoxides; D000804:Angiotensin II; D019255:NADPH Oxidases