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

Jiang, Kailun; Cao, Siyang

doi:10.4172/2155-9570.s2-007

Cited by 25 publications

(21 citation statements)

References 44 publications

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“…If RPE cells were exposed to AGE chronically, there may be a tipping point where the stresses overwhelm RPE cell's adaptive mechanisms leading to dysfunction and death. Evidence of a chronic inflammatory response in which several of the proinflammatory mediators studied here was recently shown in an immunohistochemical study of the postmortem eye with drusen [60].…”

Section: Para-inflammationsupporting

confidence: 54%

Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: Implications for age-related degenerative diseases of the eye

et al. 2013

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Age related macular degeneration (AMD) is one of the leading causes of blindness in Western society. A hallmark of early stage AMD are drusen, extracellular deposits that accumulate in the outer retina. Advanced glycation endproducts (AGE) accumulate with aging and are linked to several age-related diseases such as Alzheimer's disease, osteoarthritis, atherosclerosis and AMD. AGE deposits are found in drusen and in Bruch's membrane of the eye and several studies have suggested its role in promoting oxidative stress, apoptosis and lipofuscin accumulation. Recently, complement activation and chronic inflammation have been implicated in the pathogenesis of AMD. While AGEs have been shown to promote inflammation in other diseases, whether it plays a similar role in AMD is not known. This study investigates the effects of AGE stimulation on pro- and anti-inflammatory pathways in primary culture of human retinal pigment epithelial cells (RPE). Differential gene expression studies revealed a total of 41 up- and 18 down-regulated RPE genes in response to AGE stimulation. These genes fell into three categories as assessed by gene set enrichment analysis (GSEA). The main categories were inflammation (interferon-induced, immune response) and proteasome degradation, followed by caspase signaling. Using suspension array technology, protein levels of secreted cytokines and growth factors were also examined. Anti-inflammatory cytokines including IL10, IL1ra and IL9 were all overexpressed. Pro-inflammatory cytokines including IL4, IL15 and IFN-γ were overexpressed, while other pro-inflammatory cytokines including IL8, MCP1, IP10 were underexpressed after AGE stimulation, suggesting a para-inflammation state of the RPE under these conditions. Levels of mRNA of chemokine, CXCL11, and viperin, RSAD2, were up-regulated and may play a role in driving the inflammatory response via the NF-kB and JAK-STAT pathways. CXCL11 was strongly immunoreactive and associated with drusen in the AMD eye. The pathways and novel genes identified here highlight inflammation as a key response to AGE stimulation in primary culture of human RPE, and identify chemokine CXCL11 as putative novel agent associated with the pathogenesis of AMD.

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Section: Para-inflammationsupporting

confidence: 54%

Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: Implications for age-related degenerative diseases of the eye

et al. 2013

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“…Epithelial pulmonary cells also possess high basal RAGE expression levels [ 34 ], which could link RAGE signaling and interferon expression. In our case, IFN-γ expression, induced by AGEs–BSA exposure in a time dependent manner, could possess a biological activity similar to that of extracellular IFN-γ [ 35 ] and could act to temper the immune response by inducing STAT1 activation and STAT3 deactivation, as described in other reports [ 36 ].…”

Section: Resultssupporting

confidence: 58%

AGEs-Induced IL-6 Synthesis Precedes RAGE Up-Regulation in HEK 293 Cells: An Alternative Inflammatory Mechanism?

Serban

Stanca

Geicu

et al. 2015

IJMS

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Advanced glycation end products (AGEs) can activate the inflammatory pathways involved in diabetic nephropathy. Understanding these molecular pathways could contribute to therapeutic strategies for diabetes complications. We evaluated the modulation of inflammatory and oxidative markers, as well as the protective mechanisms employed by human embryonic kidney cells (HEK 293) upon exposure to 200 μg/mL bovine serum albumine (BSA) or AGEs–BSA for 12, 24 and 48 h. The mRNA and protein expression levels of AGEs receptor (RAGE) and heat shock proteins (HSPs) 27, 60 and 70, the activity of antioxidant enzymes and the expression levels of eight cytokines were analysed. Cell damage via oxidative mechanisms was evaluated by glutathione and malondialdehyde levels. The data revealed two different time scale responses. First, the up-regulation of interleukin-6 (IL-6), HSP 27 and high catalase activity were detected as early as 12 h after exposure to AGEs–BSA, while the second response, after 24 h, consisted of NF-κB p65, RAGE, HSP 70 and inflammatory cytokine up-regulation, glutathione depletion, malondialdehyde increase and the activation of antioxidant enzymes. IL-6 might be important in the early ignition of inflammatory responses, while the cellular redox imbalance, RAGE activation and NF-κB p65 increased expression further enhance inflammatory signals in HEK 293 cells.

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“…34 Because both T-cell lines produced IL-17 as well as IFN-c but differed in VEGF production, VEGF production by T cells is suggested to be the pivotal factor in PDSAg-induced postuveitis neovascularization, as neovascularization was observed only in the retinas of subjects with EAU induced by PDSAg but not by R14.…”

Section: Discussionmentioning

confidence: 99%

A New Small Molecule For Treating Inflammation and Chorioretinal Neovascularization in Relapsing-Remitting and Chronic Experimental Autoimmune Uveitis

Diedrichs-Möhring¹,

Leban²,

Strobl³

et al. 2014

Investigative Ophthalmology & Visual Science

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

Cited by 25 publications

References 44 publications

Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: Implications for age-related degenerative diseases of the eye

Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: Implications for age-related degenerative diseases of the eye

AGEs-Induced IL-6 Synthesis Precedes RAGE Up-Regulation in HEK 293 Cells: An Alternative Inflammatory Mechanism?

A New Small Molecule For Treating Inflammation and Chorioretinal Neovascularization in Relapsing-Remitting and Chronic Experimental Autoimmune Uveitis

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