The small tellurium-based compound SAS suppresses inflammation in human retinal pigment epithelium.
OBJECTIVE
Pathological angiogenesis and chronic inflammation greatly contribute to the development of choroidal neovascularization (CNV) in chorioretinal diseases involving abnormal contact between retinal pigment epithelial (RPE) and endothelial cells (ECs), associated with Bruch's membrane rupture. We explored the ability of the small organotellurium compound octa-O-bis-(R,R)-tartarate ditellurane (SAS) to mitigate inflammatory processes in human RPE cells.


METHODS
Cell adhesion assays and analyses of gene and protein expression were used to examine the effect of SAS on ARPE-19 cells or primary human RPE cells that were grown alone or in an RPE-EC co-culture.


RESULTS
Adhesion assays showed that SAS inhibited αv integrins expressed on RPE cells. Co-cultures of RPE cells with ECs significantly reduced the gene expression of PEDF, as compared to RPE cells cultured alone. Both SAS and the anti-αvβ3 antibody LM609 significantly enhanced the production of PEDF at both mRNA and protein levels in RPE cells. RPE cells co-cultured with EC exhibited increased gene expression of CXCL5, COX1, MMP2, IGF1, and IL8, all of which are involved in both angiogenesis and inflammation. The enhanced expression of these genes was greatly suppressed by SAS, but interestingly, remained unaffected by LM609. Zymography assay showed that SAS reduced the level of MMP-2 activity in RPE cells. We also found that SAS significantly suppressed IL-1β-induced IL-6 expression and secretion from RPE cells by reducing the protein levels of phospho-IkappaBalpha (pIκBα).


CONCLUSIONS
Our results suggest that SAS is a promising anti-inflammatory agent in RPE cells, and may be an effective therapeutic approach for controlling chorioretinal diseases.
Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; Laboratory of Eye Research, Felsenstein Medical Research Center, Petach Tikva, Israel.
Rima
R
Dardik
Laboratory of Eye Research, Felsenstein Medical Research Center, Petach Tikva, Israel.
Tami
T
Livnat
C.A.I.R. Institute, The Safdié AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Gilad
G
Halpert
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD.
Shayma
S
Jawad
Laboratory of Eye Research, Felsenstein Medical Research Center, Petach Tikva, Israel.
Yael
Y
Nisgav
Laboratory of Eye Research, Felsenstein Medical Research Center, Petach Tikva, Israel.
Shirley
S
Azar-Avivi
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD.
Baoying
B
Liu
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD.
Robert B
RB
Nussenblatt
Laboratory of Eye Research, Felsenstein Medical Research Center, Petach Tikva, Israel; Department of Ophthalmology, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Dov
D
Weinberger
C.A.I.R. Institute, The Safdié AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Benjamin
B
Sredni
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D054365:Chemokine CXCL5 / Q000378:metabolism; D018920:Coculture Techniques; D051545:Cyclooxygenase 1 / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D042783:Endothelial Cells / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D039564:Integrin alphaV / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D013644:Tartrates / Q000494:pharmacology*; D013691:Tellurium / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D000893:Anti-Inflammatory Agents; D054365:Chemokine CXCL5; D051545:Cyclooxygenase 1; D005136:Eye Proteins; D007334:Insulin-Like Growth Factor I; D039564:Integrin alphaV; D016209:Interleukin-8; D020778:Matrix Metalloproteinase 2; D009414:Nerve Growth Factors; D009942:Organometallic Compounds; D012333:RNA, Messenger; D015843:Serpins; D013644:Tartrates; D013691:Tellurium; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C486263:CXCL5 protein, human; C508606:CXCL8 protein, human; C583557:IGF1 protein, human; C467484:VEGFA protein, human; C530751:octa-O-bistartarate ditellurane; C496511:PTGS1 protein, human; C522361:MMP2 protein, human