title: High glucose and interleukin-1beta downregulate interleukin-1 type I receptor (IL-1RI) in retinal endothelial cells by enhancing its degradation by a lysosome-dependent mechanism.
abstract: Diabetic retinopathy has been considered a low-grade chronic inflammatory disease. The production of interleukin-1beta (IL-1beta) in the retina is increased, and this finding has been correlated with an increase in blood-retinal barrier permeability, suggesting that IL-1beta might have an important role in the pathogenesis of diabetic retinopathy. However, in this context, no attention has been given to interleukin-1 type I receptor (IL-1RI), which is the receptor responsible for IL-1beta triggered effects. Therefore, we investigated the effect of high glucose and IL-1beta on the IL-1RI regulation in retinal endothelial cells. A time-dependent downregulation of IL-1RI protein levels was detected in retinal endothelial cells exposed (1-24h) to high glucose, mannitol or IL-1beta. Long-term exposure (7days) to high glucose or mannitol also decreased IL-1RI protein content. IL-1RI downregulation was due to its activation by IL-1beta, since it was inhibited by the presence of anti-IL-1RI or anti-IL-1beta antibodies. Moreover, IL-1RI downregulation was prevented by lysosome inhibitors, chloroquine and ammonium chloride, but not by proteasome inhibitors, MG132 and lactacystin. We also found that IL-1RI translocates to the nucleus after high glucose or IL-1beta treatment. In conclusion, our results indicate that high glucose, probably due to osmotic stress, and IL-1beta downregulate IL-1RI in retinal endothelial cells. The downregulation of IL-1RI is triggered by its activation and is due, at least partially, to lysosomal degradation. High glucose and IL-1beta also enhance the translocation of IL-1RI to the nucleus.
authors.affiliation: Center of Ophthalmology and Vision Sciences, Institute of Biomedical Research in Light and Image, University of Coimbra, Portugal.
authors.forename: Célia
authors.initials: C
authors.lastname: Aveleira
authors.forename: Aurea
authors.initials: A
authors.lastname: Castilho
authors.forename: Filipa
authors.initials: F
authors.lastname: Baptista
authors.forename: Núria
authors.initials: N
authors.lastname: Simões
authors.forename: Carolina
authors.initials: C
authors.lastname: Fernandes
authors.forename: Ermelindo
authors.initials: E
authors.lastname: Leal
authors.forename: António Francisco
authors.initials: AF
authors.lastname: Ambrósio
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier / Q000378:metabolism; D002460:Cell Line; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism*; D008353:Mannitol / Q000494:pharmacology; D061988:Proteasome Inhibitors; D051381:Rats; D055647:Rats, Transgenic; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism*; D012160:Retina / Q000166:cytology*
chemical_list: D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D061988:Proteasome Inhibitors; D053573:Receptors, Interleukin-1 Type I; D008353:Mannitol; D005947:Glucose