Role of the JNK Signaling PathWay in Downregulation of Connexin43 by TNF-α in Human Corneal Fibroblasts

Kimura, Kazuhiro; Orita, Tetsuji; Morishige, Naoyuki; Nishida, Teruo; Sonoda, Koh Hei

doi:10.3109/02713683.2013.798419

Cited by 20 publications

(18 citation statements)

References 33 publications

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“…The MAPK signaling pathways contain highly conserved serine/threonine protein kinases that function in various fundamental cellular processes, such as growth/proliferation, differentiation, motility, and apoptosis/survival as well as the stress response and the response to infection. Several of the MAPK family members have been shown to be involved in corneal inflammation caused by adenoviruses 48 and staphylococci 49 and in certain pathological processes progressing from the corneal epithelium to the endothelium 49 – 51 . Although patients with FK have been treated with antifungal drugs that prevent the progression of corneal pathogenesis, further inflammatory reaction to the fungus still destroy the corneal tissue.…”

Section: Discussionmentioning

confidence: 99%

ROS-induced Oxidative Injury involved in Pathogenesis of Fungal Keratitis via p38 MAPK Activation

Hua

Chi

et al. 2017

Sci Rep

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This study was to explore the mechanism by which reactive oxygen species (ROS)-induced oxidative stress involved in the pathogenesis of fungal keratitis using an in vivo experimental keratitis mouse model and an in vitro culture model of human corneal epithelial cells (HCECs). Compared to normal control mice and HCECs, ROS production was markedly increased in fungal corneas and HCECs exposed to Candida albicans, accompanied by p38 mitogen-activated protein kinases (MAPK) activation. Increased products of oxidative markers, malondialdehyde (MDA), 4–hydroxynonenal (HNE), mitochondria DNA 8-OHdG and aconitase-2 were observed in fungal infected corneas and HCECs. Fungal infection also increased the mRNA expression and protein production of heme oxygenase-1 (HMOX1) and cyclooxygenase-2 (COX2), with suppressed levels of antioxidant enzymes, superoxide dismutase-1 (SOD1), glutathione peroxidase-1 (GPx1) and peroxiredoxin-4 (PRDX4). Interestingly, the levels of ROS, oxidative markers and oxygenases were significantly reduced by co-cultured p38 inhibitor SB203580. Furthermore, SB203580 restored the levels of antioxidant enzymes suppressed by fungus. Our findings demonstrated for the first time that ROS-induced oxidative injury is involved in pathogenesis of fungal keratitis via p38 MAPK pathway, suggesting the novel therapeutic targets for the potential treatment of fungal keratitis.

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Section: Discussionmentioning

confidence: 99%

ROS-induced Oxidative Injury involved in Pathogenesis of Fungal Keratitis via p38 MAPK Activation

Hua

Chi

et al. 2017

Sci Rep

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“…The important finding of the present study was that TNF-α can selectively modulate the expression of Cx43 on the VSMCs through JNK pathways. JNK and p38MAPK kinase have been reported to be important intracellular signaling pathways that regulate Cx43 (23,24). A previous study (25) investigated the effects of amphetamine on the Cx43 gene expression through the JNK-AP-1 pathway in cultured neonatal rat cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

TNF-α regulates apoptosis of human vascular smooth muscle cells through gap junctions

Tang¹,

Fang²

2017

Molecular Medicine Reports

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Inflammatory cytokines are released by immune cells and are able to induce vascular smooth muscle cells (VSMCs) to undergo apoptosis, causing atherosclerotic plaque rupture. Changes in the expression levels of connexins (Cxs) have been demonstrated in VSMCs to be involved in the pathogenesis of atherosclerotic progression. The present study examined the effect of tumor necrosis factor‑α (TNF‑α) on Cx43 expression levels and apoptosis in human VSMCs. Overexpression of Cx43 plasmids notably stimulated VSMC proliferation. TNF‑α directly inhibited Cx43 expression levels in a dose‑ and time‑dependent manner in VSMCs, however this was blocked by c‑Jun N‑terminal kinase inhibitor. TNF‑α also increased caspase‑3 activity and apoptosis of VSMCs through the inhibition of Cx43. These data suggested that TNF‑α induced the apoptosis of VMSCs and prompted the destabilization of atherosclerotic plaques by downregulating Cx43.

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“…TNFα has also been implicated to have a negative effect on Cx43. It was shown to reduce GJIC and Cx43 levels in corneal fibroblasts which was mediated by the JNK signaling pathway (Kimura and Nishida 2010 , Kimura et al 2013 ). Furthermore, TNFα inhibited Cx43 gap junctions through JNK activity (Zhang et al 2015 , Zhang et al 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of carbon nanotubes on intercellular communication and involvement of IL-1 genes

Arnoldussen

Anmarkrud

Skaug

et al. 2016

J. Cell Commun. Signal.

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An increasing amount of products containing engineered nanoparticles is emerging. Among these particles are carbon nanotubes (CNTs) which are of interest for a wide range of industrial and biomedical applications. There have been raised concerns over the effects of CNTs on human health. Some types of CNTs are classified as group 2B carcinogens by the International Agency for Research on Cancer. CNTs may also induce pulmonary inflammatory and fibrotic effects. By utilizing CNTs of different lengths, we investigated the role of the proinflammatory cytokine, interleukin-1 (IL-1) on gap junctional intercellular communication (GJIC) by using IL-1 wild-type (IL1-WT) and IL-1 knock-out (IL1-KO) cells. GJIC decreased equally in both cell types after CNT exposure. Immunofluorescence staining showed Gja1 and Gjb2 in gap junctions and hemichannels for both cell types. Gjb1 and Gjb2 expression was low in IL1-KO cells, which was confirmed by protein analysis. Gja1 was upregulated with both CNTs, whereas Gjb1 was down-regulated by CNT-2 in IL1-WT cells. Connexin mRNA expression was regulated differently by the CNTs. CNT-1 affected Gja1 and Gjb2, whereas CNT-2 had an effect on Gjb1. CNTs negatively affect GJIC through gap junctions independently of the length of CNT and IL-1 status. Furthermore, connexin gene expression was affected by IL-1 at transcriptional and translational levels. As both CNTs used in this study are cytotoxic to the cells and reduce cell survival, we suggest that CNT-induced reduction in GJIC may be important for inhibiting transfer of cell survival signals between cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s12079-016-0323-0) contains supplementary material, which is available to authorized users.

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Role of the JNK Signaling PathWay in Downregulation of Connexin43 by TNF-α in Human Corneal Fibroblasts

Abstract: The inhibitory effects of TNF-α on Cx43 expression and GJIC in human corneal fibroblasts are mediated, at least in part, by the JNK signaling pathway, which therefore likely plays a role in corneal inflammation.

Cited by 20 publications

References 33 publications

ROS-induced Oxidative Injury involved in Pathogenesis of Fungal Keratitis via p38 MAPK Activation

ROS-induced Oxidative Injury involved in Pathogenesis of Fungal Keratitis via p38 MAPK Activation

TNF-α regulates apoptosis of human vascular smooth muscle cells through gap junctions

Effects of carbon nanotubes on intercellular communication and involvement of IL-1 genes

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