Mammalian telomeric DNA suppresses endotoxin-induced uveitis.
Telomeric regions of mammalian chromosomes contain suppressive TTAGGG motifs that inhibit several proinflammatory and Th1-biased immune responses. Synthetic oligodeoxynucleotides (ODN) expressing suppressive motifs can reproduce the down-regulatory activity of mammalian telomeric repeats and have proven effective in the prevention and treatment of several autoimmune and autoinflammatory diseases. Endotoxin-induced uveitis (EIU) is an established animal model of acute ocular inflammation induced by LPS administration. Augmented expression of proinflammatory cytokines/chemokines such as TNFalpha, IL-6, and MCP1 and bactericidal nitric oxide production mediated by LPS contribute to the development of EIU. Suppressing these mediators using agents that are devoid of undesirable systemic side effects may help prevent the development of EIU. This study demonstrates the selective down-regulatory role of suppressive ODN after (i) local or (ii) systemic treatment in EIU-induced rabbits and mice. Our results indicate that suppressive ODN down-regulate at both the transcript and protein levels of several proinflammatory cytokines and chemokines as well as nitric oxide and co-stimulatory surface marker molecules when administrated prior to, simultaneously with, or even after LPS challenge, thereby significantly reducing ocular inflammation in both rabbit and mouse eyes. These findings strongly suggest that suppressive ODN is a potent candidate for the prevention of uveitis and could be applied as a novel DNA-based immunoregulatory agent to control other autoimmune or autoinflammatory diseases.
Yagci
Fuat C
FC
Biotherapeutic Oligonucleotide Laboratory, Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey.
Aslan
Ozlem
O
Gursel
Mayda
M
Tincer
Gizem
G
Ozdamar
Yasemin
Y
Karatepe
Kutay
K
Akcali
K Can
KC
Gursel
Ihsan
I
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D007155:Immunologic Factors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011817:Rabbits; D016615:Telomere; D014605:Uveitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D007155:Immunologic Factors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides