Fas/Fas ligand-associated apoptosis in experimental autoimmune uveoretinitis in rodents: role of proinflammatory corticotropin-releasing hormone.
We have previously shown that corticotropin-releasing hormone plays an important proinflammatory role in the induction of experimental autoimmune uveoretinitis. In this study, we examined the role of apoptosis in the destruction of the retina during experimental autoimmune uveoretinitis, and the role of corticotropin-releasing hormone as a local regulator of Fas and Fas Ligand expression in this condition. We evaluated apoptosis by the terminal deoxynucleotidyl transferase dUTP nick end labeling method and Fas and Fas Ligand presence by immunohistochemistry. We examined formalin-fixed, paraffin-embedded eye sections from female Lewis rats or B10.A mice immunized with the major pathogenetic epitope (R16 peptide) of the interphotoreceptor retinoid-binding protein. Female B10.A mice similarly immunized were treated with intraperitoneal injections of the rabbit anti-corticotropin-releasing hormone antibody TS-2 or nonimmune rabbit serum. The percentage of retinal cells undergoing apoptosis and the expression of Fas and Fas Ligand were increased in inflamed retinas in immunized Lewis rats and B10.A mice, compared to controls. Retinas from immunized B10.A mice treated with anti-corticotropin-releasing hormone antibody showed significantly lower apoptosis and Fas and Fas Ligand expression than placebo-treated animals. In conclusion, retinal cells in experimental autoimmune uveoretinitis undergo apoptosis associated with concurrent upregulation of Fas and Fas Ligand. The local presence of corticotropin-releasing hormone appears to be of pivotal importance in this process.
Poulaki
V
V
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Evgenidion Hospital, Athens, Greece. mitsiades@netscape.net
Mitsiades
N
N
Mastorakos
G
G
Caspi
R R
RR
Chrousos
G P
GP
Bouzas
E
E
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020274:Autoimmune Diseases of the Nervous System / Q000378:metabolism / Q000473:pathology*; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D004254:DNA Nucleotidyltransferases / Q000502:physiology; D005260:Female; D020287:In Situ Nick-End Labeling; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011917:Rats, Inbred Lew; D012173:Retinitis / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation; D014605:Uveitis / Q000378:metabolism / Q000473:pathology*; D019014:fas Receptor / Q000502:physiology*
D019014:fas Receptor; D003346:Corticotropin-Releasing Hormone; D004254:DNA Nucleotidyltransferases