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Inhibition of Noncanonical Murine Double Minute 2 Homolog Abrogates Ocular Inflammation through NF-κB Suppression
- Publication Year :
- 2018
- Publisher :
- American Society for Investigative Pathology, 2018.
-
Abstract
- Uveitis is estimated to account for 10% of all cases of blindness in the United States, including 30,000 new cases of legal blindness each year. Intraocular and oral corticosteroids are the effective mainstay treatment, but they carry the risk of serious long-term ocular and systemic morbidity. New noncorticosteroid therapies with a favorable side effect profile are necessary for the treatment of chronic uveitis, given the paucity of existing treatment choices. We have previously demonstrated that Nutlin-3, a small-molecule inhibitor of murine double minute 2 (MDM2) homolog, suppresses pathologic retinal angiogenesis through a p53-dependent mechanism, but the noncanonical p53-independent functions have not been adequately elucidated. Herein, we demonstrate an unanticipated function of MDM2 inhibition, where Nutlin-3 potently abrogates lipopolysaccharide-induced ocular inflammation. Furthermore, we identified a mechanism by which transcription and translation of NF-κB is mediated by MDM2, independent of p53, in ocular inflammation. Small-molecule MDM2 inhibition is a novel noncorticosteroid strategy for inhibiting ocular inflammation, which may potentially benefit patients with chronic uveitis.
- Subjects :
- 0301 basic medicine
Eye Diseases
Angiogenesis
Legal blindness
Apoptosis
Retinal Pigment Epithelium
Article
Piperazines
Pathology and Forensic Medicine
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Transcription (biology)
Medicine
Animals
Humans
Ocular inflammation
Cells, Cultured
Cell Proliferation
Inflammation
Mice, Knockout
biology
business.industry
Imidazoles
NF-kappa B
Retinal
NF-κB
Proto-Oncogene Proteins c-mdm2
medicine.disease
Mice, Inbred C57BL
030104 developmental biology
chemistry
Gene Expression Regulation
030220 oncology & carcinogenesis
biology.protein
Cancer research
Mdm2
Tumor Suppressor Protein p53
business
Uveitis
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....75890a16e1e5018b13b8ffb61a21bf91