Protein kinase C-zeta mediates retinal degeneration in response to TNF.
Tumor necrosis factor-alpha (TNF) has been implicated in retinal ganglion cells (RGC) degeneration in glaucoma. Atypical protein kinase C (PKC) zeta is involved in cell protection against various stresses. The aim of this study was to investigate the potential proapoptotic effects of intravitreal injections of TNF with or without PKCzeta specific inhibitor on the rat retina. TNF was injected in the vitreous of rat eyes alone or in combination with specific PKCzeta inhibitor. PKCzeta and NF-kappaB were studied by immunohistochemistry and western-blotting analysis on retina, and apoptosis quantified by the TUNEL assay. While low basal PKCzeta was observed in the control eyes, TNF induced intense expression of PKCzeta mostly in bipolar cells processes. PKCzeta staining became nuclear when TNF was coinjected with PKCzeta inhibitor. TNF alone did not induce apoptosis in the retina. Coinjection of the PKCzeta-specific inhibitor and TNF, however, induced apoptosis in the inner nuclear and ganglion cell layers. The PKCzeta-specific inhibitor unmasks retinal cells to TNF cytotoxicity showing a link between the proapoptotic effects of TNF and the antiapoptotic PKCzeta signaling pathway.
Liang
Hong
H
INSERM, U598, Physiopathology of ocular diseases: therapeutic innovations, Department of Ophthalmology, Quinze-Vingts National Ophthalmology Hospital, AP-HP, Paris Ouest School of Medicine, Paris, France.
Baudouin
Christophe
C
Behar-Cohen
Francine
F
Crisanti
Patricia
P
Omri
Boubaker
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D020287:In Situ Nick-End Labeling; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D012162:Retinal Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*; D000097782:NF-kappaB-Inducing Kinase; D000099221:Protein Kinase C zeta
D004791:Enzyme Inhibitors; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; D000099221:Protein Kinase C zeta