PKCδ–iPLA2–PGE2–PPARγ signaling cascade mediates TNF-α induced Claudin 1 expression in human lung carcinoma cells

Iitaka, Daisuke; Moodley, Serisha; Shimizu, Hiroki; Bai, Xiaohui; Liu, Mingyao

doi:10.1016/j.cellsig.2014.12.015

Cited by 30 publications

(16 citation statements)

References 50 publications

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“…However, there is no agreement in the effect of TNFα in case of other claudins. Similar to our finding, TNFα was shown to upregulate Cldn‐1 in lung, breast and pancreatic cancer cells (Kondo et al, ; Liu et al, ; Iitaka et al, ). In contrast, TNFα induced downregulation of claudin‐1, 2, and 4 in T‐84 but not Caco‐2 intestinal cells (Fischer et al, ).…”

Section: Discussionsupporting

confidence: 90%

Tumor Necrosis Factor‐α Increases Claudin‐1, 4, and 7 Expression in Tubular Cells: Role in Permeability Changes

Amoozadeh

Dan

Anwer

et al. 2017

Journal Cellular Physiology

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Tumor necrosis factor-α (TNFα), is a pathogenic cytokine in kidney disease that alters expression of claudins in tubular cells. Previously we showed that in LLC-PK cells TNFα caused a biphasic change in transepithelial resistance (TER) consisting of an early drop and recovery, followed by a late increase. However, the underlying mechanisms and the role of specific claudins in the TER effect remained incompletely understood. Here we sought to define how TNFα affects claudins 1, 4, and 7 in tubular cells and to correlate their changes with the TER effect. We show that TNFα elevates total and surface levels of Cldn-1, 4, and 7, and increases their mRNA expression through the ERK and JNK pathways. Further, JNK is also important for TNFα-induced changes in claudin-2 expression. Continuous monitoring of TER using Electric cell-substrate impedance sensing (ECIS) reveals that the two phases of the TNFα effect are differently regulated. Specifically, inhibition of the ERK or JNK pathways prevent the late TER increase, but not the early TER effect. Silencing experiments also show that Cldn-1 is necessary for the early TNFα-induced TER change, while all three claudins appear to contribute to the late TER increase. In summary, we define a central role for ERK and JNK in TNFα-induced altered claudin expression and barrier tightening. Together, our current and previous works show that the TNFα-induced early TER effect requires claudin-1, while claudin-2 decrease is a significant mediator of the late TER increase, and elevation in claudin-1, 4, and 7 contribute to a smaller extent. J. Cell. Physiol. 232: 2210-2220, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 90%

Tumor Necrosis Factor‐α Increases Claudin‐1, 4, and 7 Expression in Tubular Cells: Role in Permeability Changes

Amoozadeh

Dan

Anwer

et al. 2017

Journal Cellular Physiology

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“…Rac1, aPKCζ/λ, glycogen synthase kinase (GSK)-3α/β, and PI3K are all phosphorylated and activated in human skin keratinocytes in response to LL-37, and blockage of any enzyme with a specific inhibitor results in a substantial reduction in the TEER and a significant increase in the permeability to FITC-dextran ( 109 ) (Figure 6 B). Rac1 is a small GTPase that functions upstream of aPKCζ/λ as part of the Par3/Par6/aPKCζ/λ polarity complex, which in turn phosphorylates the C-terminal domain of occludin ( 114 ) or JAM-1 ( 115 ), promoting its assembly into the TJ complex and enhancing the barrier function ( 116 ). GSK-3α/β is involved in a number of signaling pathways ( 117 ) and is required for induction of occludin and claudin-1 in intestinal and kidney epithelial cells ( 118 ).…”

Section: Molecular Mechanisms Of Hdp Regulation Of Barrier Functionsmentioning

confidence: 99%

Regulation of the Intestinal Barrier Function by Host Defense Peptides

et al. 2015

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Intestinal barrier function is achieved primarily through regulating the synthesis of mucins and tight junction (TJ) proteins, which are critical for maintaining optimal gut health and animal performance. An aberrant expression of TJ proteins results in increased paracellular permeability, leading to intestinal and systemic disorders. As an essential component of innate immunity, host defense peptides (HDPs) play a critical role in mucosal defense. Besides broad-spectrum antimicrobial activities, HDPs promotes inflammation resolution, endotoxin neutralization, wound healing, and the development of adaptive immune response. Accumulating evidence has also indicated an emerging role of HDPs in barrier function and intestinal homeostasis. HDP deficiency in the intestinal tract is associated with barrier dysfunction and dysbiosis. Several HDPs were recently shown to enhance mucosal barrier function by directly inducing the expression of multiple mucins and TJ proteins. Consistently, dietary supplementation of HDPs often leads to an improvement in intestinal morphology, production performance, and feed efficiency in livestock animals. This review summarizes current advances on the regulation of epithelial integrity and homeostasis by HDPs. Major signaling pathways mediating HDP-induced mucin and TJ protein synthesis are also discussed. As an alternative strategy to antibiotics, supplementation of exogenous HDPs or modulation of endogenous HDP synthesis may have potential to improve intestinal barrier function and animal health and productivity.

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“…ERK pathway is one of the wellknown pathways involved in cell migration [30] and PKCδ has been shown to mediate migration via ERK pathway in ovarian cancer cells [31]. PKCδ also enhances migration and motility of many other cell types [32][33][34][35]. TGFβ, an endogenous cancer-related growth factor, had similar effect on cellular phenotype as PMA on control cells, while again glycodelin-producing cells remained unresponsive.…”

Section: Discussionmentioning

confidence: 99%

Repressed PKCδ activation in glycodelin-expressing cells mediates resistance to phorbol ester and TGFβ

Hautala

Koistinen

2016

Cellular Signalling

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Glycodelin is a glycoprotein mainly expressed in well-differentiated epithelial cells in reproductive tissues. In normal secretory endometrium, the expression of glycodelin is abundant and regulated by progesterone. In hormone-related cancers glycodelin expression is associated with well-differentiated tumors. We have previously found that glycodelin drives epithelial differentiation of HEC-1B endometrial adenocarcinoma cells, resulting in reduced tumor growth in a preclinical mouse model. Here we show that glycodelin-transfected HEC-1B cells have repressed protein kinase C delta (PKCδ) activation, likely due to downregulation of PDK1, and are resistant to phenotypic change and enhanced migration induced by phorbol 12-myristate 13-acetate (PMA). In control cells, which do not express glycodelin, the effects of PMA were abolished by using PKCδ and PDK1 inhibitors, and knockdown of PKCδ, MEK1 and 2, or ERK1 and 2 by siRNAs. Similarly, transforming growth factor β (TGFβ)-induced phenotypic change was only seen in control cells, not in glycodelin-producing cells, and it was mediated by PKCδ. Taken together, these results strongly suggest that PKCδ, via MAPK pathway, is involved in the glycodelin-driven cell differentiation rendering the cells resistant to stimulation by PMA and TGFβ.

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PKCδ–iPLA2–PGE2–PPARγ signaling cascade mediates TNF-α induced Claudin 1 expression in human lung carcinoma cells

Cited by 30 publications

References 50 publications

Tumor Necrosis Factor‐α Increases Claudin‐1, 4, and 7 Expression in Tubular Cells: Role in Permeability Changes

Tumor Necrosis Factor‐α Increases Claudin‐1, 4, and 7 Expression in Tubular Cells: Role in Permeability Changes

Regulation of the Intestinal Barrier Function by Host Defense Peptides

Repressed PKCδ activation in glycodelin-expressing cells mediates resistance to phorbol ester and TGFβ

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