Skip to main content
Erschienen in: Journal of Neuroinflammation 1/2018

Open Access 01.12.2018 | Research

LncRNA H19 contributes to hippocampal glial cell activation via JAK/STAT signaling in a rat model of temporal lobe epilepsy

verfasst von: Chun-Lei Han, Ming Ge, Yun-Peng Liu, Xue-Min Zhao, Kai-Liang Wang, Ning Chen, Wen-Jia Meng, Wei Hu, Jian-Guo Zhang, Liang Li, Fan-Gang Meng

Erschienen in: Journal of Neuroinflammation | Ausgabe 1/2018

Abstract

Background

Astrocyte and microglia activation are well-known features of temporal lobe epilepsy that may contribute to epileptogenesis. However, the mechanisms underlying glia activation are not well understood. Long non-coding RNA (lncRNA) H19 has diverse functions depending on physiological or pathological state, and its role in epilepsy is unknown. We previously demonstrated that H19 was significantly upregulated in the latent period of epilepsy and may be associated with cell proliferation and immune and inflammatory responses. We therefore speculated that H19 is involved in the hippocampal glial cell activation during epileptogenesis.

Methods

H19 was overexpressed or knocked down using an adeno-associated viral vector delivery system. A rat status epilepticus model was induced by intra-amygdala kainic acid injection. Astrocyte and microglia activation were assessed by immunofluorescence and western blot analyses. Expression of proinflammatory cytokines and components of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways were evaluated with western blotting.

Results

H19 overexpression induced the activation of astrocytes and microglia and the release of proinflammatory cytokines (interleukin-1β and interleukin-6 and tumor necrosis factor-α) in the hippocampus, whereas H19 knockdown inhibited status epilepticus-induced glial cell activation. Moreover, H19 activated JAK/STAT signaling by promoting the expression of Stat3 and c-Myc, which is thought to be involved in astrocyte activation.

Conclusions

LncRNA H19 contributes to hippocampal glial cell activation via modulation of the JAK/STAT pathway and could be a therapeutic tool to prevent the development of epilepsy.
Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12974-018-1139-z) contains supplementary material, which is available to authorized users.
Abkürzungen
AAV
Adeno-associated viral
CNS
Central nervous system
DAPI
4′,6-diamidino-2-phenylin-dole
GAPDH
Glyceraldehyde 3-phosphate dehydrogenase
GFAP
Glial fibrillary acidic protein
IL
Interleukin
JAK
Janus kinase
KA
Kainic acid
lncRNA
Long non-coding RNA
NC
Negative control
NeuN
Neuronal nuclei
Nrf
Nuclear respiratory factor
p-Stat3
Phosphorylated Stat3
SE
Status epilepticus
shRNA
Short hairpin RNA
STAT
Signal transducer and activator of transcription
TLE
Temporal lobe epilepsy
TNF
Tumor necrosis factor

Background

Temporal lobe epilepsy (TLE) is one of the most common types of intractable epilepsy and is characterized by the periodic and unpredictable occurrence of seizures. Glial cell activation and proliferation, a well-described pathological feature of TLE, can alter blood-brain barrier integrity and ion and neurotransmitter homeostasis and cause an inflammatory response, resulting in neuronal hyperexcitability and the generation and spread of seizure activity [13]. Although impairment of these functions is thought to be associated with the pathophysiology of epilepsy, the mechanisms underlying glial cell activation are complex and are not fully understood [1].
Long non-coding RNA (lncRNA) H19, an imprinted gene, is located on human chromosome 11 and is transcribed from the maternally inherited allele [4]. Despite being identified over 20 years ago, the function of H19 remains unclear and its pathological role as a non-coding RNA has only recently been elucidated [5]. H19 has diverse functions depending on physiological and pathological state. In the central nervous system (CNS), H19 is overexpressed in glioblastoma tissue and promotes the proliferation, differentiation, migration, and invasion of glioma cells [6, 7]. However, the biological function of H19 in non-neoplastic CNS diseases including epilepsy remains unknown.
We previously showed by high-throughput microarray and bioinformatics analyses that H19 is upregulated in the latent period of TLE in rat and is involved in various aspects of epileptogenesis, including cell proliferation and immune and inflammatory responses [8]. We therefore speculated that H19 may be involved in hippocampal glial cell activation during epileptogenesis. This was investigated in the present study by gain- and loss-of-function studies in a rat model of TLE. We also examined the possible downstream targets of H19.

Methods

Animal and human samples

Male Sprague–Dawley rats weighing 200–220 g were obtained from Vital River Experimental Animal Technology Co. (Beijing, China) and were housed in a temperature-controlled room with free access to standard food and water under a 12:12-h light/dark cycle. Surgically resected hippocampus specimens were obtained from patients with intractable TLE who underwent surgical treatment at Beijing Tiantan Hospital. Control hippocampal tissue was obtained from autopsies of four patients without a history of epilepsy or other neurological diseases within 8 h after death.

H19 overexpression and knockdown

H19 was overexpressed or silencing using an adeno-associated viral (AAV) vector delivery system as previously described [8]. Briefly, a vector harboring H19 (AAV-H19) or a short hairpin RNA targeting H19 (AAV-shRNA) was constructed by Gene Chem Co. (Shanghai, China). The negative control was an empty AAV vector (AAV-NC) or one harboring a scrambled sequence (AAV-Scr: 5′-TTCTCCGAACGTGTCACGT-3′). The titers used were 1.0 × 1012 for AAV9-H19 and 4.0 × 1012 for AAV9-shRNA. A total of 6 μl AAV was infused into the right dorsal hippocampus (3.12 mm posterior to the bregma, 3.0 mm lateral to the midline, and 3.4 mm ventral to the bregma) and ventral hippocampus (5.04 mm posterior to the bregma, 5.0 mm lateral to the midline, and 6.4 mm ventral to the bregma; 3 μl at each location) [9] through a microsyringe at a speed of 0.2 μl/min.

Epilepsy model

A kainic acid (KA)-induced status epilepticus (SE) model was established by intra-amygdala microinjection of KA 14 days after AAV injection according to our previously described technique [8]. Briefly, the rats were placed in a stereotaxic apparatus (David Kopf Instruments, Tujunga, CA, USA), and 0.7 μl KA (1 μg/μl; Sigma–Aldrich, St. Louis, MO, USA) was injected into the right amygdala (2.76 mm posterior to the bregma, 4.5 mm lateral to the midline, and 8.6 mm ventral to the bregma) [9] at a speed of 0.2 μl/min. Sham-operated controls were injected with an equal volume of saline.

Immunofluorescence analysis

Coronal sections (25 μm) were prepared at the level of the dorsal hippocampus (2.50–3.50 mm posterior to the bregma). Frozen sections were dried, washed, permeabilized, blocked in 5% goat serum, and incubated overnight with antibodies against neuronal nuclei (NeuN) (ab177487, 1:500 and ab104224, 1:200), glial fibrillary acidic protein (GFAP) (ab7260, 1:500), and OX42 (ab1211, 1:100) (all from Abcam, Cambridge, MA, USA). Immunolabeled sections were washed and incubated with goat secondary antibodies conjugated with Alexa Fluor 594 or Alexa Fluor 488 (Merck Biosciences, Nottingham, UK). Sections were mounted with medium containing 4′,6-diamidino-2-phenylin-dole (DAPI) (Vector Laboratories, Burlingame, CA, USA), and images were captured using an inverted fluorescence microscope (Olympus, Tokyo, Japan). GFAP+ or OX42+ cells were manually counted using ImageJ software (US National Institutes of Health, Bethesda, MD, USA).

Western blotting

Western blot analysis was performed as previously described [10] using the following primary antibodies: rabbit polyclonal anti-GFAP (ab7260, 1:1000), mouse monoclonal anti-OX42 (ab1211, 1:500), rabbit polyclonal anti-interleukin (IL)-1β (ab9722; 1:500), mouse monoclonal anti-IL-6 (ab9324; 1:500), rabbit polyclonal anti-tumor necrosis factor (TNF)-α (ab6671; 1:500), rabbit monoclonal anti-p-Stat3 (ab76315; 1:500), and rabbit polyclonal anti-c-Myc (ab39688; 1:500) (all from Abcam, Cambridge, MA, USA). Rabbit monoclonal anti-glyceraldehyde 3-phosphate dehydrogenase (GAPDH) antibody (Abcam, ab181602, 1:3000) was used as a control. Protein band density was quantified using an Epson V330 Photo scanner (Seiko Epson Co., Nagano, Japan) and Quantity One software (Bio-Rad, Hercules, CA, USA).

Statistical analysis

Data are presented as mean ± standard error of the mean. Two-group comparisons were made with the unpaired Student’s t test, and multi-group comparisons were made by one-way analysis of variance followed by Sidak’s multiple comparison tests using Prism 5 software (GraphPad Inc., San Diego, CA, USA). Significance was accepted at P < 0.05.

Results

Astrocytes and microglia are activated in the hippocampus of epileptic rats

We first examined GFAP and OX42 expression in the hippocampus of epileptic rats by immunofluorescence analysis to evaluate astrocyte and microglia activation, respectively. GFAP and OX42 immunoreactivity was detected in the ipsilateral hippocampus 7 days (latent period) (Figs. 2 and 3) or 30 days (chronic period) (Fig. 1) after KA-induced SE. The number of GFAP+ cells was increased, and activated astrocytes showed hypertrophy with a large cytoplasm and thick processes. The number of OX42+ cells was also increased, and the morphology of the activated microglia changed from spindle shape to oval with thickened processes. Fewer activated glial cells were observed in the contralateral as compared in the ipsilateral hippocampus (Fig. 1).

H19 is involved in the activation of astrocytes and microglia in the hippocampus of epileptic rats

Our previous study showed that H19 has diverse functions related to epileptogenesis [8] and is highly expressed in the seizure-free latent period of TLE. In the present study, we investigated the role of H19 in astrocyte and microglia activation by H19 overexpression and knockdown using an AAV delivery system [8]. Astrocyte and microglial activation were evaluated by GFAP and OX42 immunofluorescence and western blot analyses. Compared to the sham group (NC + Veh or Scr + Veh), KA-induced SE (KA + Veh) or H19 overexpression (H19 + Veh) alone induced the activation of astrocytes or microglia in the stratum radiatum of the hippocampal CA3 region (Figs. 2 and 3). Moreover, more activated cells were observed in the hippocampus of rats overexpressing H19 at 7 days after SE (H19 + KA). The observed SE-induced activation of astrocytes and microglia was partly inhibited by H19 knockdown (ShRNA + KA vs Scr + KA). A quantitative analysis of GFAP and OX42 protein levels in the hippocampal CA3 region at 7 days (Figs. 2 and 3) and 60 days (Additional file 1: Figure S1) after SE confirmed these results.
We also examined proinflammatory cytokines released from the activated glia. H19 overexpression and KA-induced SE both stimulated the release of IL-1β and IL-6 and TNF-α in the CA3 subfield of the hippocampus (Fig. 4a). Cytokine release was further increased by H19 at 7 days after SE (Fig. 4a). H19 knockdown prevented the SE-induced increase in IL-1β and IL-6 and TNF-α levels (Fig. 4b). These results indicate that H19 plays an important role in astrocyte and microglia activation during epileptogenesis.

H19 induces astrocyte and microglia activation via JAK/STAT signaling

Stat3 plays a key role in astrocyte proliferation after central nervous system injury [11, 12] or SE [13]. We found here that the levels of phosphorylated Stat3 (p-Stat3) and its downstream effector c-Myc were upregulated in hippocampal tissue samples from patients with TLE (Fig. 5a) and from rats 7 days after SE (Fig. 5b) relative to the respective control samples, as determined with western blotting, suggesting that Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is involved in the activation of glial cells after SE. H19 overexpression alone increased p-Stat3 and c-Myc protein levels in the CA3 subfield of the hippocampus (Fig. 5c). H19 exacerbated these protein expressions in the rats at 7 days (Fig. 5c) and 60 days (Additional file 2: Figure S2A) after SE. On the contrary, H19 knockdown abolished the SE-induced increase in p-Stat3 and c-Myc in rats at 7 days (Fig. 5d) and 60 days (Additional file 2: Figure S2B) after SE. These results indicate that H19 promotes astrocyte and microglial activation via the JAK/STAT signaling pathway.

Discussion

Most previous studies on H19 function focused on tumorigenesis. H19 was initially proposed as a tumor suppressor due to its capacity to suppress clonogenicity and tumorigenicity in tumor cells [14, 15]. However, recent studies showed that H19 acts as an oncogene by promoting cell proliferation, migration, invasion, and metastasis in various malignancies including glioblastoma [1618]. Apart from these functions, H19 is also implicated in several other physiological conditions or diseases, such as cartilage degeneration in osteoarthritis [19], skeletal muscle differentiation and regeneration [20], and glucose metabolism in muscle cells [21]. However, the role of H19 in non-neoplastic CNS diseases including epilepsy remains unclear. In the present study, we provide the first evidence that H19 promotes glial cell activation and stimulates inflammation in the hippocampus of rats with TLE.
Astrocyte activation is a continuum that includes changes in molecular expression, progressive cellular hypertrophy, and, in severe cases, proliferation and scar formation [22]. In mild or moderate astrocyte activation, GFAP expression is slightly upregulated and the cell body and processes undergo hypertrophy, with little or no astrocyte proliferation. However, in severe diffuse reactive astrogliosis, GFAP expression is markedly increased, which is accompanied by extensive hypertrophy of the cell body and processes and astrocyte proliferation [23]. In the present study, astrocytes in the hippocampus of epileptic rats were activated in the latent and chronic phases of TLE, which is consistent with previous reports [13, 24]. Mild to moderate gliosis, which typically does not cause astrocyte proliferation, is usually observed in the early stages after SE [25]. We also found that astrocyte activation was mild or moderate, as evidenced by the upregulation of GFAP expression and cellular hypertrophy without an obvious increase in cell number in the latent period of TLE (7 days after SE). Furthermore, H19 induced an increase in GFAP expression and hypertrophy of astrocytes rather than cell proliferation in the latent period of SE. In the chronic period (30 days after SE), astrocyte activation was extreme with severe hypertrophy of the cell body and processes; moreover, astrocyte proliferation in areas of pyramidal neuron loss was comparable to the hippocampal sclerosis observed in TLE patients [26]. Unlike astrocytes, high expression of OX42 protein and cellular hypertrophy as well as proliferation of microglia was observed in both the latent and chronic periods of TLE, as previously reported [27]. Furthermore, H19 induced the upregulation of OX42 and cellular hypertrophy and increased the number of microglia in the latent period of SE. Recent studies have shown that inflammatory cytokines are produced both by microglia and astrocytes [28]; the increased levels of proinflammatory cytokines in epileptic rats observed here is in agreement with these findings. Moreover, H19 stimulated the release of proinflammatory cytokines. However, compared to sham rats, H19 knockdown did not inhibit proinflammatory cytokine expression, possibly because under normal conditions, proinflammatory cytokine levels in the hippocampus are too low to result in an observable difference upon H19 knockdown.
Molecular triggers that lead to glial cell activation and proliferation have not been fully characterized. There is increasing evidence to suggest that H19 has a growth-promoting function, since it enhances cell proliferation in tumors [29, 30] and other diseases [20, 31]. In the present study, we showed that H19 promotes astrocyte and microglia activation and proliferation under both epileptic and normal conditions. This is consistent with earlier reports as well as with our previous research [8]. Various intracellular signaling pathways associated with Stat3, nuclear factor κB, and nuclear respiratory factor (Nrf) mediate cell hypertrophy, proliferation, and pro- or anti-inflammatory effects in astrocytes [23]. The transcription factor Stat3, a key component of the JAK/STAT pathway, is important for astrocyte proliferation in CNS diseases [11, 32, 33]. P-Stat3 is highly expressed in the rat hippocampus during different phases of epilepsy and in the temporal lobe of TLE patients [13]. Astrocyte activation can be suppressed by inhibiting JAK/STAT signaling, indicating that Stat3 activation induces GFAP expression [13]. In our study, Stat3 as well as its downstream effector c-Myc in the JAK/STAT pathway were upregulated after SE in the rat hippocampus and in TLE patients. Furthermore, H19 overexpression induced whereas its knockdown inhibited Stat3 and c-Myc protein expression in both normal and epileptic rats. Thus, H19 can itself promote gliosis via JAK/STAT signaling in addition to its role in astrocyte activation.

Conclusions

In summary, lncRNA H19 contributes to the activation of hippocampal astrocytes and microglia, as well as to the inflammatory response in epileptic rats. Furthermore, H19 may promote glial cell activation through the JAK/STAT pathway. Our findings reveal a novel lncRNA H19-mediated mechanism in seizure-induced glial cell activation and provide a basis for developing lncRNA-based strategies to prevent the development of epilepsy.

Acknowledgements

Not applicable

Funding

This study was supported by the National Natural Science Foundation of China (81471315).

Availability of data and materials

All data are provided in the manuscript and in the additional files.
All experimental protocols involving animals were in compliance with the Chinese Animal Welfare Act and Beijing Guidelines for the Care and Use of Laboratory Animals. Written informed consent was obtained from each patient for the use of brain tissue for research purposes. The protocol was approved by the Ethics Committee of Beijing Neurosurgical Institute, Capital Medical University (process no. 201402019).
Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.
Literatur
1.
Zurück zum Zitat Seifert G, Carmignoto G, Steinhauser C. Astrocyte dysfunction in epilepsy. Brain Res Rev. 2010;63:212–21.CrossRefPubMed Seifert G, Carmignoto G, Steinhauser C. Astrocyte dysfunction in epilepsy. Brain Res Rev. 2010;63:212–21.CrossRefPubMed
2.
Zurück zum Zitat Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 2009;32:421–31.CrossRefPubMed Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 2009;32:421–31.CrossRefPubMed
3.
4.
Zurück zum Zitat Pachnis V, Belayew A, Tilghman SM. Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes. Proc Natl Acad Sci U S A. 1984;81:5523–7.CrossRefPubMedPubMedCentral Pachnis V, Belayew A, Tilghman SM. Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes. Proc Natl Acad Sci U S A. 1984;81:5523–7.CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Liang WC, Fu WM, Wong CW, Wang Y, Wang WM, Hu GX, Zhang L, Xiao LJ, Wan DC, Zhang JF, Waye MM. The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer. Oncotarget. 2015;6:22513–25.PubMedPubMedCentral Liang WC, Fu WM, Wong CW, Wang Y, Wang WM, Hu GX, Zhang L, Xiao LJ, Wan DC, Zhang JF, Waye MM. The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer. Oncotarget. 2015;6:22513–25.PubMedPubMedCentral
6.
Zurück zum Zitat Jiang X, Yan Y, Hu M, Chen X, Wang Y, Dai Y, Wu D, Wang Y, Zhuang Z, Xia H. Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells. J Neurosurg. 2016;124:129–36.CrossRefPubMed Jiang X, Yan Y, Hu M, Chen X, Wang Y, Dai Y, Wu D, Wang Y, Zhuang Z, Xia H. Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells. J Neurosurg. 2016;124:129–36.CrossRefPubMed
7.
Zurück zum Zitat Jia P, Cai H, Liu X, Chen J, Ma J, Wang P, Liu Y, Zheng J, Xue Y. Long non-coding RNA H19 regulates glioma angiogenesis and the biological behavior of glioma-associated endothelial cells by inhibiting microRNA-29a. Cancer Lett. 2016;381:359–69.CrossRefPubMed Jia P, Cai H, Liu X, Chen J, Ma J, Wang P, Liu Y, Zheng J, Xue Y. Long non-coding RNA H19 regulates glioma angiogenesis and the biological behavior of glioma-associated endothelial cells by inhibiting microRNA-29a. Cancer Lett. 2016;381:359–69.CrossRefPubMed
8.
Zurück zum Zitat Han CL, Liu YP, Zhao XM, Wang KL, Chen N, Hu W, Zhang JG, Ge M, Meng FG. Whole-transcriptome screening reveals the regulatory targets and functions of long non-coding RNA H19 in epileptic rats. Biochem Biophys Res Commun. 2017;489:262–9.CrossRefPubMed Han CL, Liu YP, Zhao XM, Wang KL, Chen N, Hu W, Zhang JG, Ge M, Meng FG. Whole-transcriptome screening reveals the regulatory targets and functions of long non-coding RNA H19 in epileptic rats. Biochem Biophys Res Commun. 2017;489:262–9.CrossRefPubMed
9.
Zurück zum Zitat Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 5th ed. San Diego: Elsevier Academic Press; 2005. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 5th ed.  San Diego: Elsevier Academic Press; 2005.
10.
Zurück zum Zitat Wu X, Sun J, Zhang X, Li X, Liu Z, Yang Q, Li L. Epigenetic signature of chronic cerebral hypoperfusion and beneficial effects of S-adenosylmethionine in rats. Mol Neurobiol. 2014;50:839–51.CrossRefPubMed Wu X, Sun J, Zhang X, Li X, Liu Z, Yang Q, Li L. Epigenetic signature of chronic cerebral hypoperfusion and beneficial effects of S-adenosylmethionine in rats. Mol Neurobiol. 2014;50:839–51.CrossRefPubMed
11.
Zurück zum Zitat Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK, Korsak RA, Takeda K, Akira S, Sofroniew MV. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci. 2008;28:7231–43.CrossRefPubMedPubMedCentral Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK, Korsak RA, Takeda K, Akira S, Sofroniew MV. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci. 2008;28:7231–43.CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Tsuda M, Kohro Y, Yano T, Tsujikawa T, Kitano J, Tozaki-Saitoh H, Koyanagi S, Ohdo S, Ji RR, Salter MW, Inoue K. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain. 2011;134:1127–39.CrossRefPubMedPubMedCentral Tsuda M, Kohro Y, Yano T, Tsujikawa T, Kitano J, Tozaki-Saitoh H, Koyanagi S, Ohdo S, Ji RR, Salter MW, Inoue K. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain. 2011;134:1127–39.CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Xu Z, Xue T, Zhang Z, Wang X, Xu P, Zhang J, Lei X, Li Y, Xie Y, Wang L, et al. Role of signal transducer and activator of transcription-3 in up-regulation of GFAP after epilepsy. Neurochem Res. 2011;36:2208–15.CrossRefPubMed Xu Z, Xue T, Zhang Z, Wang X, Xu P, Zhang J, Lei X, Li Y, Xie Y, Wang L, et al. Role of signal transducer and activator of transcription-3 in up-regulation of GFAP after epilepsy. Neurochem Res. 2011;36:2208–15.CrossRefPubMed
14.
Zurück zum Zitat Hao Y, Crenshaw T, Moulton T, Newcomb E, Tycko B. Tumour-suppressor activity of H19 RNA. Nature. 1993;365:764–7.CrossRefPubMed Hao Y, Crenshaw T, Moulton T, Newcomb E, Tycko B. Tumour-suppressor activity of H19 RNA. Nature. 1993;365:764–7.CrossRefPubMed
15.
Zurück zum Zitat Yoshimizu T, Miroglio A, Ripoche MA, Gabory A, Vernucci M, Riccio A, Colnot S, Godard C, Terris B, Jammes H, Dandolo L. The H19 locus acts in vivo as a tumor suppressor. Proc Natl Acad Sci U S A. 2008;105:12417–22.CrossRefPubMedPubMedCentral Yoshimizu T, Miroglio A, Ripoche MA, Gabory A, Vernucci M, Riccio A, Colnot S, Godard C, Terris B, Jammes H, Dandolo L. The H19 locus acts in vivo as a tumor suppressor. Proc Natl Acad Sci U S A. 2008;105:12417–22.CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Yan L, Zhou J, Gao Y, Ghazal S, Lu L, Bellone S, Yang Y, Liu N, Zhao X, Santin AD, et al. Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation. Oncogene. 2015;34:3076–84.CrossRefPubMed Yan L, Zhou J, Gao Y, Ghazal S, Lu L, Bellone S, Yang Y, Liu N, Zhao X, Santin AD, et al. Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation. Oncogene. 2015;34:3076–84.CrossRefPubMed
17.
Zurück zum Zitat Shi Y, Wang Y, Luan W, Wang P, Tao T, Zhang J, Qian J, Liu N, You Y. Long non-coding RNA H19 promotes glioma cell invasion by deriving miR-675. PLoS One. 2014;9:e86295.CrossRefPubMedPubMedCentral Shi Y, Wang Y, Luan W, Wang P, Tao T, Zhang J, Qian J, Liu N, You Y. Long non-coding RNA H19 promotes glioma cell invasion by deriving miR-675. PLoS One. 2014;9:e86295.CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, Galun E. The H19 non-coding RNA is essential for human tumor growth. PLoS One. 2007;2:e845.CrossRefPubMedPubMedCentral Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, Galun E. The H19 non-coding RNA is essential for human tumor growth. PLoS One. 2007;2:e845.CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Steck E, Boeuf S, Gabler J, Werth N, Schnatzer P, Diederichs S, Richter W. Regulation of H19 and its encoded microRNA-675 in osteoarthritis and under anabolic and catabolic in vitro conditions. J Mol Med (Berl). 2012;90:1185–95.CrossRef Steck E, Boeuf S, Gabler J, Werth N, Schnatzer P, Diederichs S, Richter W. Regulation of H19 and its encoded microRNA-675 in osteoarthritis and under anabolic and catabolic in vitro conditions. J Mol Med (Berl). 2012;90:1185–95.CrossRef
20.
Zurück zum Zitat Dey BK, Pfeifer K, Dutta A. The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration. Genes Dev. 2014;28:491–501.CrossRefPubMedPubMedCentral Dey BK, Pfeifer K, Dutta A. The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration. Genes Dev. 2014;28:491–501.CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Gao Y, Wu F, Zhou J, Yan L, Jurczak MJ, Lee HY, Yang L, Mueller M, Zhou XB, Dandolo L, et al. The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells. Nucleic Acids Res. 2014;42:13799–811.CrossRefPubMedPubMedCentral Gao Y, Wu F, Zhou J, Yan L, Jurczak MJ, Lee HY, Yang L, Mueller M, Zhou XB, Dandolo L, et al. The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells. Nucleic Acids Res. 2014;42:13799–811.CrossRefPubMedPubMedCentral
22.
Zurück zum Zitat Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35.CrossRefPubMed Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35.CrossRefPubMed
24.
Zurück zum Zitat Shapiro LA, Wang L, Ribak CE. Rapid astrocyte and microglial activation following pilocarpine-induced seizures in rats. Epilepsia. 2008;49(Suppl 2):33–41.CrossRefPubMed Shapiro LA, Wang L, Ribak CE. Rapid astrocyte and microglial activation following pilocarpine-induced seizures in rats. Epilepsia. 2008;49(Suppl 2):33–41.CrossRefPubMed
25.
Zurück zum Zitat Gibbons MB, Smeal RM, Takahashi DK, Vargas JR, Wilcox KS. Contributions of astrocytes to epileptogenesis following status epilepticus: opportunities for preventive therapy? Neurochem Int. 2013;63:660–9.CrossRefPubMed Gibbons MB, Smeal RM, Takahashi DK, Vargas JR, Wilcox KS. Contributions of astrocytes to epileptogenesis following status epilepticus: opportunities for preventive therapy? Neurochem Int. 2013;63:660–9.CrossRefPubMed
27.
Zurück zum Zitat Avignone E, Ulmann L, Levavasseur F, Rassendren F, Audinat E. Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling. J Neurosci. 2008;28:9133–44.CrossRefPubMed Avignone E, Ulmann L, Levavasseur F, Rassendren F, Audinat E. Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling. J Neurosci. 2008;28:9133–44.CrossRefPubMed
28.
Zurück zum Zitat Rizzi M, Perego C, Aliprandi M, Richichi C, Ravizza T, Colella D, Veliskova J, Moshe SL, De Simoni MG, Vezzani A. Glia activation and cytokine increase in rat hippocampus by kainic acid-induced status epilepticus during postnatal development. Neurobiol Dis. 2003;14:494–503.CrossRefPubMed Rizzi M, Perego C, Aliprandi M, Richichi C, Ravizza T, Colella D, Veliskova J, Moshe SL, De Simoni MG, Vezzani A. Glia activation and cytokine increase in rat hippocampus by kainic acid-induced status epilepticus during postnatal development. Neurobiol Dis. 2003;14:494–503.CrossRefPubMed
29.
Zurück zum Zitat Tan D, Wu Y, Hu L, He P, Xiong G, Bai Y, Yang K. Long noncoding RNA H19 is up-regulated in esophageal squamous cell carcinoma and promotes cell proliferation and metastasis. Dis Esophagus. 2017;30:1–9. Tan D, Wu Y, Hu L, He P, Xiong G, Bai Y, Yang K. Long noncoding RNA H19 is up-regulated in esophageal squamous cell carcinoma and promotes cell proliferation and metastasis. Dis Esophagus. 2017;30:1–9.
30.
Zurück zum Zitat Iempridee T. Long non-coding RNA H19 enhances cell proliferation and anchorage-independent growth of cervical cancer cell lines. Exp Biol Med (Maywood). 2017;242:184–93.CrossRef Iempridee T. Long non-coding RNA H19 enhances cell proliferation and anchorage-independent growth of cervical cancer cell lines. Exp Biol Med (Maywood). 2017;242:184–93.CrossRef
31.
Zurück zum Zitat Xu X, Ji S, Li W, Yi B, Li H, Zhang H, Ma W. LncRNA H19 promotes the differentiation of bovine skeletal muscle satellite cells by suppressing Sirt1/FoxO1. Cell Mol Biol Lett. 2017;22:10.CrossRefPubMedPubMedCentral Xu X, Ji S, Li W, Yi B, Li H, Zhang H, Ma W. LncRNA H19 promotes the differentiation of bovine skeletal muscle satellite cells by suppressing Sirt1/FoxO1. Cell Mol Biol Lett. 2017;22:10.CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Satriotomo I, Bowen KK, Vemuganti R. JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia. J Neurochem. 2006;98:1353–68.CrossRefPubMed Satriotomo I, Bowen KK, Vemuganti R. JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia. J Neurochem. 2006;98:1353–68.CrossRefPubMed
33.
Zurück zum Zitat Ben Haim L, Ceyzeriat K, Carrillo-de Sauvage MA, Aubry F, Auregan G, Guillermier M, Ruiz M, Petit F, Houitte D, Faivre E, et al. The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer’s and Huntington’s diseases. J Neurosci. 2015;35:2817–29.CrossRefPubMed Ben Haim L, Ceyzeriat K, Carrillo-de Sauvage MA, Aubry F, Auregan G, Guillermier M, Ruiz M, Petit F, Houitte D, Faivre E, et al. The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer’s and Huntington’s diseases. J Neurosci. 2015;35:2817–29.CrossRefPubMed
Metadaten
Titel
LncRNA H19 contributes to hippocampal glial cell activation via JAK/STAT signaling in a rat model of temporal lobe epilepsy
verfasst von
Chun-Lei Han
Ming Ge
Yun-Peng Liu
Xue-Min Zhao
Kai-Liang Wang
Ning Chen
Wen-Jia Meng
Wei Hu
Jian-Guo Zhang
Liang Li
Fan-Gang Meng
Publikationsdatum
01.12.2018
Verlag
BioMed Central
Erschienen in
Journal of Neuroinflammation / Ausgabe 1/2018
Elektronische ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1139-z

Weitere Artikel der Ausgabe 1/2018

Journal of Neuroinflammation 1/2018 Zur Ausgabe