JNK and ERK MAP kinases mediate induction of IL-1β, TNF-α and IL-8 following hyperosmolar stress in human limbal epithelial cells

Li, Dequan; Luo, Lihui; Chen, Zhuo; Kim, Hyun Seung; Song, Xiu Jun; Pflugfelder, Stephen C.

doi:10.1016/j.exer.2005.08.019

Cited by 302 publications

(228 citation statements)

References 39 publications

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“…This initiates the vicious circle of dry eye pathology in a final common pathway. Hyperosmolarity induces inflammatory cascade activation [135][136][137], increases apoptosis [138][139][140], and stimulates expression and activity of MMPs [141,142], causing ocular surface barrier disruption [143,144]. In severe cases, dry eye also leads to squamous metaplasia involving ocular surface epithelial cell transdifferentiation from a wet mucosal phenotype to a keratinized skin-like phenotype [145].…”

Section: Ocular Surface Barrier Function In Dry Eye Diseasementioning

confidence: 99%

Clusterin in the eye: An old dog with new tricks at the ocular surface

Fini

Bauskar

Jeong

et al. 2016

Experimental Eye Research

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, M. R. (2016). Clusterin in the eye: an old dog with new tricks at the ocular surface. Experimental Eye Research, Clusterin in the eye: an old dog with new tricks at the ocular surface AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had been demonstrated throughout the body, including in the eye. Its homeostatic activities in proteostasis, cytoprotection, and anti-inflammation have been well documented, however its roles in health and disease are still not well understood. CLU is prominent at fluid-tissue interfaces, and in 1996 it was demonstrated to be the most highly expressed transcript in the human cornea, the protein product being localized to the apical layers of the mucosal epithelia of the cornea and conjunctiva. CLU protein is also present in human tears. Using a preclinical mouse model for desiccating stress that mimics human dry eye disease, the authors recently demonstrated that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration in the tears. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to LGALS3 (galectin-3), a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. CLU depletion from the ocular surface epithelia is seen in a variety of inflammatory conditions in humans and mice that lead to squamous metaplasia and a keratinized epithelium. This suggests that CLU might have a specific role in maintaining mucosal epithelial differentiation, an idea that can now be tested using the mouse model for desiccating stress. Most excitingly, the new findings suggest that CLU could serve as a novel biotherapeutic for dry eye disease. Competing Interests: US patent 9,241,974 B2 entitled "Clusterin pharmaceuticals and treatment methods using the same" (inventors: MEF and SJ), assigned to the University of Southern California, is connected with this work. MEF holds a management position with Proteris Biotech, Inc., Pasadena, CA, which is developing Protearin for dry eye based on clusterin. MRW declares that he has no competing interests. Page 3 of 65 AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had bee...

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Section: Ocular Surface Barrier Function In Dry Eye Diseasementioning

confidence: 99%

Clusterin in the eye: An old dog with new tricks at the ocular surface

Fini

Bauskar

Jeong

et al. 2016

Experimental Eye Research

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“…В результате лечения КС уменьшается площадь окрашивания роговицы флюорес-цеином, исчезают эпителиальные нити, снижаются уров-ни IL-1β, IL-6, IL-8, ММП-9 и митоген-активированных протеинкиназ в эпителии глазной поверхности [16,31]. КС способны также подавлять активность c-Jun-N-терминала киназ (JNK) и внеклеточно регулируемых ки-наз, которые опосредуют увеличение экспрессии провос-палительных цитокинов и хемокинов, и, соответственно, уменьшать воспаление в лимбальном эпителии роговицы [12]. Противовоспалительный ответ на терапию КС до-стигается в более короткие сроки, чем на терапию CsA.…”

Section: цели терапии сккunclassified

“…В отличие от них доксициклин и миноциклин имеют бо-лее длительный период действия (15-17 ч), что позволяет использовать их реже [16]. Доксициклин способен инак-тивировать JNK и внеклеточно регулируемые киназы и, соответственно, уменьшать активность воспаления в эпи-телии лимбальной зоны роговицы [12]. Он подавляет так-же экспрессию ММП-9, IL-1α, IL-1β и TNF-α в эпителии роговицы.…”

Section: цели терапии сккunclassified

“…Митоген-активированные протеинкиназы, в свою очередь, стимулируют продукцию противовоспали-тельных цитокинов и ММП, в том числе IL-β, TNF-α, ММП-3 и ММП-9 [10,11]. ММП (особая роль принадле-жит ММП-9) лизируют компоненты эпителия роговицы и способствуют нарушению его целостности [11,12].…”

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Treating severe keratoconjunctivitis sicca

Gladkova

Safonova

2015

Vestn. oftal'mol.

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Сухой кератоконъюнктивит (СКК), или синдром «су-хого глаза», широко распространен в мире и является од-ной из актуальных проблем современной офтальмологии. По данным российских исследователей, этим заболевани-ем страдают до 12% больных офтальмологического про-филя в возрасте до 40 лет и свыше 67% пациентов старше 50 лет. За последние 30 лет частота обнаружения синдрома «сухого глаза» возросла в 4,5 раза [1].СКК оказывает существенное влияние на качество жизни больных из-за выраженности субъективных сим-птомов: жжения, ощущения инородного тела и «песка», сухости и боли в глазах, нарушения зрения. Это приводит к снижению производительности труда, особенно при вы-полнении работы, требующей зрительных нагрузок. Тя-желые формы СКК по степени выраженности болевого синдрома сопоставимы со среднетяжелыми формами сте-нокардии [2].По мнению ведущих специалистов в этой области, се-годня не существует эффективной терапии СКК, что свя-зано с многофакторным патогенезом заболевания [3]. И только углубленное исследование патогенетических механизмов данного заболевания позволят разработать новые направления эффективных методов его лечения.Патогенез. Согласно определению, принятому на Международном симпозиуме по синдрому сухого глаза (2007; The International Dry Eye Workshop), СКК -это мультифакторное заболевание, сопровождающееся повы-шением осмолярности слезы и воспалением глазной по-верхности, приводящее к появлению симптомов диском-форта, нарушению зрения и дестабилизации слезной пленки [4]. По выраженности клинических проявлений выделяют легкую, среднюю, тяжелую и особо тяжелую степени СКК. Клиническими проявлениями тяжелой степени СКК являются: нитчатый и буллезно-нитчатый кератит, рецидивирующая микроэрозия роговицы. Тече-

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“…Another subfamily-p44/42 MAPK-is primarily responsible for transduction of mitogenic signals induced by growth factor; inhibition of p44/42MAPK activity accelerates cell death (Lee et al, 2005). However, in human limbal epithelial cells, hyperosmolarity-induced activation of the p44/42MAPK pathway induces inflammation (Li et al, 2006). These considerations suggest that the dynamic balance between the growth factor-activated p44/42MAPK pathway and the stress-activated p38MAPK and SAPK/JNK pathways is cell-type specific and may be critical for determining whether a cell survives or undergoes apoptosis (Xia et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Fate of hypertonicity-stressed corneal epithelial cells depends on differential MAPK activation and p38MAPK/Na–K–2Cl cotransporter1 interaction

Capó-Aponte

Wang

Bildin

et al. 2007

Experimental Eye Research

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The capacity of the corneal epithelium to adapt to hypertonic challenge is dependent on the ability of the cells to upregulate the expression and activity of cell membrane-associated Na-K-2Cl cotransporter1 (NKCC1). Yet, the signaling pathways that control this response during hypertonic stress are still unclear. We studied stress-induced changes in proliferation and survival capacity of SV40-immortalized human (HCEC) and rabbit (RCEC) corneal epithelial cells as a function of (i) the magnitude of the hypertonic challenge, (ii) differential changes in activation of mitogen-activated protein kinase (MAPK), and (iii) the extent of p38MAPK interaction with NKCC1. Cells were incubated in hypertonic (up to 600 mOsm) media for varying time periods up to 24 h. Phosphorylated forms of p44/42, p38, and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) MAPK were immunoprecipitated from cell lysates, and the amount of each activated NKCC1-associated MAPK was evaluated by Western blot/ECL assay. DNA integrity was assessed by electrophoresis in a 2% agarose gel. Cell survival and proliferation were evaluated based on three criteria: protein content, cell count, and the MTT assay. Exposure to media of 325-350 mOsm increased proliferation of HCEC up to 75%, whereas this response was limited to <16% in RCEC. At higher osmolarities, cell proliferation decreased in both species. SAPK/JNK activity increased 150-fold in HCEC and <10-fold in RCEC, while DNA fragmentation occurred only in HCEC. Compared to HCEC, the better RCEC survival rate was associated with higher p38MAPK activity and near complete restoration of p44/42MAPK activity after the first 30 min. In both cell lines, the amount of phospho-NKCC1 that coimmunoprecipitated with phospho-p38MAPK was proportional to the magnitudes of their respective activation levels. However, no such associations occurred between amounts of phosphorylated p44/42MAPK or SAPK/JNK and phospho-NKCC1. Under isotonic conditions, with bumetanide-induced inhibition of RCEC and HCEC NKCC1 activities, p44/42MAPK activity declined by 40 and 60%, respectively. Such declines led to proportional decreases in cell proliferation. Survival of hypertonicity-stressed corneal epithelial cells depends both on p38MAPK activation capacity and the ability of p38MAPK to stimulate NKCC1 activity through protein-protein interaction. The level of NKCC1 activation affects the extent of cell volume recovery and, in turn, epithelial survival capacity.

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JNK and ERK MAP kinases mediate induction of IL-1β, TNF-α and IL-8 following hyperosmolar stress in human limbal epithelial cells

Cited by 302 publications

References 39 publications

Clusterin in the eye: An old dog with new tricks at the ocular surface

Clusterin in the eye: An old dog with new tricks at the ocular surface

Treating severe keratoconjunctivitis sicca

Fate of hypertonicity-stressed corneal epithelial cells depends on differential MAPK activation and p38MAPK/Na–K–2Cl cotransporter1 interaction

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