Role of macrophage migration inhibitory factor (MIF) in the effects of oxidative stress on human retinal pigment epithelial cells

Ko, Ji‐Ae; Sotani, Yasuyuki; Ibrahim, Diah Gemala; Kiuchi, Yoshiaki

doi:10.1002/cbf.3292

Cited by 11 publications

(7 citation statements)

References 31 publications

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“…Consistent with our findings, Huang et al found delayed reformation of tight junctions in a diabetic rat model [17]. It is well documented in other cell types that increased oxidative stress can result in decreased expression of tight junction proteins [37][38][39][40]. In the present study, not only did antioxidant treatment restore CEC proliferation and migration under diabetic conditions, NAC also improved both TEER values and ZO-1 expression.…”

Section: Discussionsupporting

confidence: 93%

Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling

et al. 2019

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Corneal wounds usually heal quickly; but diabetic patients have more fragile corneas and experience delayed and painful healing. In the present study, we compared the healing capacity of corneal epithelial cells (CECs) between normal and diabetic conditions and the potential mechanisms. Primary murine CEC derived from wild-type and diabetic (db/db) mice, as well as primary human CEC were prepared. Human CEC were exposed to high glucose (30 mM) to mimic diabetic conditions. Cell migration and proliferation were assessed using Scratch test and MTT assays, respectively. Reactive oxygen species (ROS) production in the cells was measured using dichlorofluorescein reagent. Western blot was used to evaluate the expression levels of Akt. Transepithelial electrical resistance (TEER) and zonula occludens-1 (ZO-1) expression were used to determine tight junction integrity. We found that the diabetic CEC displayed significantly slower cell proliferation and migration compared with the normal CEC from both mice and humans. Furthermore, ROS production was markedly increased in CEC grown under diabetic conditions. Treatment with an antioxidant N-acetyl cysteine (NAC, 100 μM) significantly decreased ROS production and increased wound healing in diabetic CEC. Barrier function was significantly reduced in both diabetic mouse and human CEC, while NAC treatment mitigated these effects. We further showed that Akt signaling was impaired in diabetic CEC, which was partially improved by NAC treatment. These results show that diabetic conditions lead to delayed wound-healing capacity of CEC and impaired tight junction formation in both mice and human. Increased ROS production and inhibited Akt signaling may contribute to this outcome, implicating these as potential targets for treating corneal wounds in diabetic patients.

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Section: Discussionsupporting

confidence: 93%

Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling

et al. 2019

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“…The assay was conducted as previously described 14,31,43,45 with some modifications. The assay was conducted as previously described 14,31,43,45 with some modifications.…”

Section: Collagen Gel Contraction Assay (Threedimensional Cell Cultmentioning

confidence: 99%

An in vitro study of scarring formation mediated by human Tenon fibroblasts: Effect of Y‐27632, a Rho kinase inhibitor

Ibrahim

Iwata

et al. 2019

Cell Biochemistry & Function

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Scar formation is the most common cause for failure of glaucoma filtration surgery because of increased fibroblast proliferation and activation. We have now examined the effect of Y‐27632, a Rho‐associated protein kinase (ROCK) inhibitor, on postsurgical scarring formation in human Tenon fibroblasts (HTFs). Collagen gel contraction assay was used to compare contractility activity of Y‐27632 with several antiglaucoma drugs. Immunofluorescence and western blotting were used to examine expression of scar formation–related factors. We found that Y‐27632 inhibited collagen gel contraction, as well as α‐smooth muscle actin and vimentin expression; these were promoted by treatment with latanoprost, timolol, or transforming growth factor (TGF)–β. To investigate the effect of Y‐27632 in postsurgical scarring, we mimicked TGF‐β secretion by stimulating HTFs with TGF‐β prior to Y‐27632 treatment. HTFs cultured in the presence of TGF‐β significantly increased gel contraction. In contrast, when HTFs were treated with 10μM Y‐27632, contraction was significantly inhibited. Furthermore, Y‐27632 reduced TGF‐β–induced phosphorylation of mitogen‐activated protein kinase signalling. These results suggest that ROCK inhibitors may inhibit fibrosis by inhibiting transdifferentiation of Tenon fibroblasts into myofibroblasts and by inhibiting TGF‐β signalling after surgery through mitogen‐activated protein kinase pathway suppression. These results implicate that ROCK inhibitors may improve outcomes after filtering surgery with a potential antiscarring effect, while latanoprost and timolol may induce fibrosis. Significance of the study Scar formation is the primary cause of failure after glaucoma filtration surgery. A ROCK inhibitor, Y‐27632, has been introduced as a novel potential antiglaucoma treatment to reduce intraocular pressure. The aim of our study was to elucidate the effect of Y‐27632 on scarring formation after glaucoma filtration surgery, in direct comparison with other antiglaucoma drugs. Our findings thus suggested that Y‐27632 may inhibit fibrosis and improve outcome after glaucoma filtration surgery through inhibition of transdifferentiation of Tenon fibroblasts into myofibroblasts, and the TGF‐β and MAPK signalling after surgery, while latanoprost and timolol may induce fibrosis.

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“…Furthermore, the level of MiF has been found to be upregulated in the vitreous in PVr patients (22). recent results implicate MiF in the induction of epithelial-mesenchymal transition (eMT) and its related processes by oxidative stress in human RPE cells, and MIF was reported to regulate expression of EMT markers (41). In the present study, our data revealed that recombinant MiF increased the expression of IL-6 and MCP-1 in human RPE cells, which suggests that MIF plays a proinflammatory role in the development of PVR.…”

Section: Discussionmentioning

confidence: 94%

Effect of macrophage migration inhibitory factor on inflammatory cytokines and fibrogenic gene expression in human RPE cells

2019

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Proliferative vitreoretinopathy (PVr) is a vision-threatening disease. it is also a common complication resulting from surgery to correct rhegmatogenous retinal detachment. Proliferation and migration of retinal pigment epithelial (rPe) cells and the secretion of extracellular matrix molecules play an important role in the formation of the preretinal membrane in PVr patients. Furthermore, upregulated expression of inflammatory cytokines within the vitreous or subretinal fluid of patients experiencing vitreoretinal disorders may aggravate the inflammatory response and be involved in the development of PVR. PVR is triggered by many inflammatory cytokines and growth factors. Macrophage migration inhibitory factor (MIF), an inflammatory cytokine, is upregulated in the vitreous in PVR patients. However, there is little known concerning the connection between MIF and the expression of inflammatory cytokines, interleukin-6 (IL-6) and monocyte chemotactic-1 (MCP-1), and the fibrogenic gene, collagen I, in human rPe cells. cell proliferation, migration, and expression of il-6, McP-1 and collagen i were assessed using an MTT assay, a Transwell assay, real-time Pcr analysis and eliSa kits. Western-blot analysis was used to detect phosphorylation of p38 mitogen activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) signaling pathways. The data revealed that MiF promoted the proliferation, migration and expression of il-6, McP-1 and collagen i, and phosphorylation of p38 and ERK signaling pathways in RPE cells in vitro. These findings suggest that MIF plays a proinflammatory and profibrotic role in the development of PVR.

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Role of macrophage migration inhibitory factor (MIF) in the effects of oxidative stress on human retinal pigment epithelial cells

Cited by 11 publications

References 31 publications

Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling

Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling

An in vitro study of scarring formation mediated by human Tenon fibroblasts: Effect of Y‐27632, a Rho kinase inhibitor

Effect of macrophage migration inhibitory factor on inflammatory cytokines and fibrogenic gene expression in human RPE cells

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