Anti-Inflammatory Effect of the Proteasome Inhibitor Bortezomib on Endotoxin-Induced Uveitis in Rats

Chen, Fang-Ting; Liu, Yichun; Yang, Chung-May; Yang, Chang-Hao

doi:10.1167/iovs.12-9505

Cited by 31 publications

(29 citation statements)

References 41 publications

(53 reference statements)

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“…45 Notably, activation of β 5i chymotrypsin-like activity has been recently reported to be involved in the generation and sustainment of an inflammatory environment, 11, 12, 48 whereas the use of inhibitors of this activity, such as bortezomib, has been described in many cancer therapies, 49, 50 neurodegenerative disorders 51 and other chronic inflammatory conditions. 52 We also observed that bortezomib completely restores the levels of the cytokines and inflammatory mediators induced by ethanol in WT brain cortices, thus corroborating the role of ethanol in UPS impairment.…”

Section: Discussionsupporting

confidence: 74%

TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain

et al. 2014

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New evidence indicates the involvement of protein degradation dysfunctions in neurodegeneration, innate immunity response and alcohol hepatotoxicity. We recently demonstrated that ethanol increases brain proinflammatory mediators and causes brain damage by activating Toll-like receptor 4 (TLR4) signaling in glia. However, it is uncertain if the ubiquitin-proteasome and autophagy-lysosome pathways are involved in ethanol-induced brain damage and whether the TLR4 response is implicated in proteolytic processes. Using the cerebral cortex of WT and TLR4-knockout mice with and without chronic ethanol treatment, we demonstrate that ethanol induces poly-ubiquitinated proteins accumulation and promotes immunoproteasome activation by inducing the expression of β2i, β5i and PA28α, although it decreases the 20S constitutive proteasome subunits (α2, β5). Ethanol also upregulates mTOR phosphorylation, leading to a downregulation of the autophagy-lysosome pathway (ATG12, ATG5, cathepsin B, p62, LC3) and alters the volume of autophagic vacuoles. Notably, mice lacking TLR4 receptors are protected against ethanol-induced alterations in protein degradation pathways. In summary, the present results provide the first evidence demonstrating that chronic ethanol treatment causes proteolysis dysfunctions in the mouse cerebral cortex and that these events are TLR4 dependent. These findings could provide insight into the mechanisms underlying ethanol-induced brain damage.

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Section: Discussionsupporting

confidence: 74%

TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain

et al. 2014

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“…15,16 Thus, we asked whether NF-jB signaling is involved in the doxycycline-mediated inhibition of peritoneal macrophages. We found that stimulation of macrophages with LPS increased phosphorylated NF-jBp65 protein expression, whereas doxycycline treatment significantly inhibited phos- phorylated NF-jBp65 expression in macrophages (Fig.…”

Section: Doxycycline Inhibits the Release Of Proinflammatory Mediatormentioning

confidence: 99%

Doxycycline Attenuates Endotoxin-Induced Uveitis by Prostaglandin E2-EP4 Signaling

Huang

Chen

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Huang J, Su W, Chen X, et al. Doxycycline attenuates endotoxin-induced uveitis by prostaglandin E2-EP4 signaling. Invest Ophthalmol Vis Sci. 2015;56:6686-6693. DOI:10.1167/ iovs.15-17045 PURPOSE. We explored the anti-inflammatory effects of doxycycline in experimental uveitis and the underlying mechanisms.METHODS. Rats with endotoxin-induced uveitis (EIU) received doxycycline (1.5 mg/kg) or the control vehicle via intraperitoneal injection. Clinical scores were graded under a slit lamp. Rat peritoneal macrophages were used in vitro to further explore the anti-inflammatory mechanisms of doxycycline. The levels of nitric oxide (NO), TNF-a, IL-1b, prostaglandin E2 (PGE2), cyclooxygenase (COX)-2, I kappa B-a (IjB-a), inducible nitric oxide synthase (iNOS), Akt, caspase-3, and nuclear factor-kappa B (NF-jB) were analyzed.RESULTS. Treatment with doxycycline dramatically reduced the clinical scores of EIU (P < 0.001), with significant decreases in inflammatory cell infiltration, protein concentrations, and the production of NO, TNF-a, and IL-1b in the aqueous humor (AqH). In vitro, doxycycline significantly inhibited the production of NO, IL-1b, and TNF-a in peritoneal macrophages by modulating the PI3K/Akt/IjB-a/NF-jB pathway. Importantly, we found that doxycycline significantly enhanced COX2 expression and PGE2 production both in vivo and in vitro. More importantly, blockade of the EP4 receptor of PGE2 significantly reversed the doxycycline-mediated inhibition of macrophages and the PI3K/Akt pathway in vitro. Furthermore, simultaneous injection of an EP4 antagonist and doxycycline significantly blocked the doxycycline-mediated attenuation of EIU.CONCLUSIONS. Doxycycline can ameliorate EIU, and PGE2-EP4 signaling is essential for the antiinflammatory effects of doxycycline in vitro and in vivo.

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“…It is approved by the FDA for use in the treatment of multiple myeloma [33]. We have demonstrated that bortezomib had anti-inflammatory effects in endotoxin-induced uveitis of rats in a previous study [34]. Concerning retinal IR injury, we hypothesized that bortezomib could inhibit the activation of NF-κB and associated inflammatory mediators, alleviate oxidative stress in the retina and reduce retinal neuron death and ganglion cell apoptosis.…”

Section: Introductionmentioning

confidence: 95%

The Protective Effects of the Proteasome Inhibitor Bortezomib (Velcade) on Ischemia-Reperfusion Injury in the Rat Retina

Chen

Yang

2013

PLoS ONE

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PurposeTo evaluate the protective effects of bortezomib (Velcade) on ischemia-reperfusion (IR) injury in the rat retina.MethodsThe rats were randomized to receive treatment with saline, low-dose bortezomib (0.05 mg/kg), or high-dose bortezomib (0.2 mg/kg) before the induction of IR injury. Electroretinography (ERG) was used to assess functional changes in the retina. The expression of inflammatory mediators (iNOS, ICAM-1, MCP-1, TNF-α), anti-oxidant proteins (heme oxygenase, thioredoxin, peroxiredoxin), and pro-apoptotic proteins (p53, bax) were quantified by PCR and western blot analysis. An immunofluorescence study was performed to detect the expression of iNOS, oxidative markers (nitrotyrosine, 8-OHdG, acrolein), NF-κB p65, and CD 68. Apoptosis of retinal cells was labeled with in situ TUNEL staining. Neu-N staining was performed in the flat-mounted retina to evaluate the density of retinal ganglion cells.ResultsERG showed a decreased b-wave after IR injury, and pretreatment with bortezomib, especially the high dosage, reduced the functional impairment. Bortezomib successfully reduced the elevation of inflammatory mediators, anti-oxidant proteins, pro-apoptotic proteins and oxidative markers after IR insult in a dose-dependent manner. In a similar fashion, NF-κB p65- and CD 68-positive cells were decreased by bortezomib treatment. Retinal cell apoptosis in each layer was attenuated by bortezomib. The retinal ganglion cell density was markedly decreased in the saline and low-dose bortezomib groups but was not significantly changed in the high-dose bortezomib group.ConclusionsBortezomib had a neuro-protective effect in retinal IR injury, possibly by inhibiting the activation of NF-κB related to IR insult and reducing the inflammatory signals and oxidative stress in the retina.

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Anti-Inflammatory Effect of the Proteasome Inhibitor Bortezomib on Endotoxin-Induced Uveitis in Rats

Cited by 31 publications

References 41 publications

TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain

TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain

Doxycycline Attenuates Endotoxin-Induced Uveitis by Prostaglandin E2-EP4 Signaling

The Protective Effects of the Proteasome Inhibitor Bortezomib (Velcade) on Ischemia-Reperfusion Injury in the Rat Retina

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