Interferon β Affects Retinal Pigment Epithelial Cell Proliferation via Protein Kinase C Pathways

Qiao, Hong; Sakamoto, Taiji; Hinton, David R.; Gopalakrishna, Rayudu; Ishibashi, Tatsuro; Ryan, Stephen J.; Inomata, Hajime

doi:10.1159/000050897

Cited by 11 publications

(7 citation statements)

References 12 publications

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“…The utility of IFN-β was found to be more promising as it promotes proliferation and repair of damaged RPE and regression of CNV in monkey AMD models. More studies on the effectiveness of IFN-β have been published in literature [38][39][40][41]. Taken together, these studies indicate the importance of IFNs in AMD pathogenesis.…”

Section: Is Ifn-γ a Possible Target For Treatment Of Amd?mentioning

confidence: 94%

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy

Jiang¹,

Cao²

2012

J Clin Exp Ophthalmol

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Age-related macular degeneration (AMD) is a neurodegenerative disease characterized by retinal cell atrophy, and/or choroidal neovascularization in the macula and constitutes the most common cause of blindness among the elderly in industrialized countries. The management of AMD is constrained by our insufficient knowledge of its underlying mechanisms. Recent studies point towards an emerging involvement of interferon-gamma (IFN-γ), a soluble cytokine associated with innate and adaptive immunity. IFN-γ promotes proinflammatory responses by activating proinflammatory cytokines and chemokines, thereby recruiting immune cells such as macrophages and T cells. On the other hand, IFN-γ modulates inflammatory response by upregulating antiinflammatory factors or inhibiting development of immune cells related to autoimmune response. The complex role of IFN-γ in AMD pathogenesis is intriguing and worth further investigation in terms of therapeutic development.

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Section: Is Ifn-γ a Possible Target For Treatment Of Amd?mentioning

confidence: 94%

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy

Jiang¹,

Cao²

2012

J Clin Exp Ophthalmol

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“…In contrast, PKC-␦ has been proposed to have predominantly proapoptotic actions, as it is cleaved and activated by caspase 3 (21)(22)(23)(24). In addition, PKC has been implicated in mediating the actions of type 1 IFN in other cell systems (32), and PKC-␦ has been identified as the serine kinase responsible for type 1 IFN-mediated phosphorylation of STAT1 (33). The possible involvement of PKC isoenzymes was determined initially by assessing the translocation of PKC isoenzymes to the cell membrane fraction, which is an indicator of enzyme activation.…”

Section: Alternative Pi3k Targets Are Activated By Ifn-␤mentioning

confidence: 99%

Inhibition of Neutrophil Apoptosis by Type 1 IFN Depends on Cross-Talk Between Phosphoinositol 3-Kinase, Protein Kinase C-δ, and NF-κB Signaling Pathways

Wang

Scheel‐Toellner

Wong

et al. 2003

The Journal of Immunology

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Neutrophils are abundant, short-lived leukocytes with a key role in the defense against rapidly dividing bacteria. They enter apoptosis spontaneously within 24–48 h of leaving the bone marrow. However, their life span can be extended during inflammatory responses by several proinflammatory cytokines. Inappropriate survival of neutrophils contributes to chronic inflammation and tissue damage associated with diseases such as rheumatoid arthritis. We have previously reported that type I IFNs can inhibit both cytokine deprivation and Fas-induced apoptosis in activated T cells. IFN-β locally produced by hyperplastic fibroblasts within the pannus tissue of patients with rheumatoid arthritis contributes to the inappropriately extended life span of infiltrating T cells. Type I IFNs are equally effective at delaying spontaneous apoptosis in human neutrophils. In the work presented here we investigated the signaling pathways involved in mediating this effect. The antiapoptotic actions of IFN-β were targeted at an early stage of neutrophil apoptosis, occurring upstream of mitochondrial permeability transition, and were phosphatidylinositol 3-kinase (PI3K) dependent, as they were blocked by the PI3K inhibitor LY294002. Analysis of signaling pathways downstream of PI3K revealed that the antiapoptotic effect of type 1 IFN was inhibited by rottlerin, SN50, and cycloheximide, indicating requirements for activation of protein kinase C-δ, NF-κB, and de novo protein synthesis, respectively. Moreover, EMSA was used to show that the activation of NF-κB occurred downstream of PI3K and protein kinase C-δ activation. We conclude that type I IFNs inhibit neutrophil apoptosis in a PI3K-dependent manner, which requires activation of protein kinase C-δ and induction of NF-κB-regulated genes.

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“…5 Protein kinase C (PKC) is a multigene family of phospholipid-dependent serine-threonine kinases that mediates the phosphorylation of numerous protein substrates in signal transduction and plays a central role in cellular processes such as proliferation, differentiation, mitosis, and inflammatory reaction. 6,7 It has been well documented that the PKC family is involved in the processes of proliferation, migration, phagocytosis, and gel contraction in RPE cells, [8][9][10][11][12][13][14] which are all reportedly implicated in the pathogenesis of PVR. We have also found that hypericin, a specific inhibitor of PKC, has potential as a therapeutic drug for PVR through its inhibition of the Ca 2+ influx pathway.…”

Section: Introductionmentioning

confidence: 99%

The inhibitory effect of small interference RNA protein kinase C-alpha on the experimental proliferative vitreoretinopathy induced by dispase in mice

Gao¹,

Wang²,

Lan³

et al. 2013

IJN

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Aim:To evaluate the effects of small interference RNA protein kinase C-alpha (siRNA-PKCα) on experimental proliferative vitreoretinopathy (PVR) induced by dispase in mice. Methods: C57BL/6 mice PVR models (4-6 weeks old) were induced by intravitreal injection of dispase and then equally divided into six groups. After 1 week, the five treatment groups received 2 µL intravitreal injections of siRNA-PKCα at a concentration of 250 nM, 500 nM, 750 nM, 1000 nM, and 1500 nM, respectively, while the negative control group received 2 µL of 500 nM no-silencing siRNA. SiRNA-PKCα was transfected by a square wave electroporator. Postoperative ophthalmic observations of lens clarity and the fundus of the eyes were performed periodically. The eyeballs of the mice were enucleated and imbedded in optimal cutting temperature to perform histological and immunofluorescence analysis at the end of a 4-week observation period. Results: Four weeks after the siRNA-PKCα injections, there are 100% lens dissolution and 100% PVR in the 250 nM group and 70%, 70%, 70%, and 50% PVR in the 500 nM, 750 nM, 1000 nM, and 1500 nM groups, respectively, which is significantly different from the negative group. Abnormalities in fundus appearance were related to the concentrations of siRNA-PKCα; a higher concentration of siRNA-PKCα resulted in a more normal fundus. Histological sections by hematoxylin-eosin staining of the eyes support the clinical observation. Immunofluorescence analysis showed that RPE65, glutamine synthase, glial acidic fibrillary protein, and α-smooth muscle actin were increasing in the retina with the decreasing concentration of siRNA-PKCα, indicating that intraocular siRNA-PKCα can partly inhibit changes of markers for glia cells, fibroblast cells, retinal pigment epithelium cells, and Müller cells in the process of PVR. Conclusion: Gene therapy with siRNA-PKCα could effectively inhibit PVR in mice and provide us with a novel therapeutic target on PVR.

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Interferon β Affects Retinal Pigment Epithelial Cell Proliferation via Protein Kinase C Pathways

Cited by 11 publications

References 12 publications

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy

Inhibition of Neutrophil Apoptosis by Type 1 IFN Depends on Cross-Talk Between Phosphoinositol 3-Kinase, Protein Kinase C-δ, and NF-κB Signaling Pathways

The inhibitory effect of small interference RNA protein kinase C-alpha on the experimental proliferative vitreoretinopathy induced by dispase in mice

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