15-Deoxy-12,14-prostaglandin J2 inhibits interferon gamma induced MHC class II but not class I expression on ARPE cells through a PPAR gamma independent mechanism.
Retinal pigment epithelial (RPE) cells constitute the external part of the blood-retinal-barrier and play a pivotal role in the regulation of retinal immunity. In the present work, we investigated the effects of 15-deoxy-12,14-prostaglandin J2 (15 PGJ2), an endogenous ligand of PPARgamma, on the IFNgamma-induced expression of MHC class II on RPE cells. Indeed, pathological expression of MHC class II molecules at the surface of RPE cells is a common feature of many blinding conditions. We demonstrated that 15 PGJ2 inhibited the IFNgamma-mediated induction of MHC class II on RPE cells without affecting the level of MHC class I and CD54 expression. The other PPARgamma agonist rosiglitazone or troglitazone had no similar effects. Moreover, the inhibitory effect of 15 PGJ2 was not abrogated by co-incubation with PPARgamma antagonists and did not involve the modulation of STAT-1, AKT or ERK1/2 phosphorylation, nor CIITA, IRF1 or IRF2 transcription. In conclusion, 15 PGJ2 inhibits strongly and specifically the IFNgamma-induced MHC class II expression on RPE cells by a PPARgamma independent mechanism. Given the differential role of MHC classes I and II in the development of autoimmune uveitis and the potential toxicity of 15 PGJ2, our data's suggest that the development of novel small molecules targeting similar PPARgamma independent pathways would be useful for the future management of uveitis.
Willermain
François
F
Department of Ophthalmology, CHU Saint-Pierre and Brugmann, Belgium. fwillerm@ulb.ac.be
Dulku
Simon
S
Gonzalez
Nathalie Suarez
NS
Blero
Daniel
D
Driessens
Gregory
G
De Graef
Chantal
C
Caspers
Laure
L
Bruyns
Catherine
C
D002460:Cell Line; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D018920:Coculture Techniques; D015237:Dinoprost / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006681:HLA-D Antigens / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D050836:Interferon Regulatory Factor-2 / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010857:Pigment Epithelium of Eye / Q000166:cytology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077154:Rosiglitazone; D050791:STAT Transcription Factors / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics; D000077288:Troglitazone
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D004791:Enzyme Inhibitors; D006681:HLA-D Antigens; D015395:Histocompatibility Antigens Class I; C494257:IRF1 protein, human; C494229:IRF2 protein, human; D007155:Immunologic Factors; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D047495:PPAR gamma; D050791:STAT Transcription Factors; D045162:Thiazolidinediones; D015534:Trans-Activators; D000077154:Rosiglitazone; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D015237:Dinoprost; D048049:Extracellular Signal-Regulated MAP Kinases; D000077288:Troglitazone; D015230:Prostaglandin D2