Regulation of CX3CL1 Expression in Human First-Trimester Decidual Cells: Implications for Preeclampsia

C-X3-C motif ligand 1 (CX3CL1) mediates migration, survival, and adhesion of natural killer (NK) cells, monocytes, and T-cells to endothelial/epithelial cells. Aberrant numbers and/or activation of these decidual immune cells elicit preeclampsia development. Decidual macrophages and NK cells are critical for implantation, while macrophage-derived tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and NK cell-derived interferon-γ (IFN-γ) are associated with preeclampsia development. Thus, serum and decidual levels of CX3CL1 from first-trimester pregnancy and preeclampsia-complicated term pregnancy were examined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The effects of incubating primary human first-trimester decidual cells (FTDCs) with estradiol + medroxyprogesterone acetate + either IL-1β or TNF-α and/or IFN-γ on CX3CL1 expression were also assessed by quantitative reverse transcription-polymerase chain reaction and ELISA. The inhibition of each signaling pathway with each kinase and nuclear factor κB (NFκB) inhibitors was evaluated by ELISA. Chemotaxis of CD56brightCD16− NK cells by various concentrations of CX3CL1 was evaluated. C-X3-C motif ligand 1 is expressed by both cytotrophoblasts and decidual cells in first-trimester decidua. C-X3-C motif ligand 1 expression is increased in term decidua but unchanged in first-trimester and term serum of patients with preeclampsia. Interferon-gamma and either IL-1β or TNF-α synergistically upregulated CX3CL1 expression in FTDCs. Coincubation with IL-1β or TNF-α or IFN-γ, mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), c-JUN N-terminal kinase (JNK), and NFκB inhibitors suppressed CX3CL1 production. C-X3-C motif ligand 1 elicited concentration-dependent enhancement of CD56brightCD16− NK cell migration. In conclusion, the current study suggests that decidual cell-secreted CX3CL1 is involved in the later development of preeclampsia, whereas circulating CX3CL1 levels do not predict preeclampsia. Mitogen-activated protein kinase kinase 1 and 2, JNK, and NFκB signaling mediate IL-1β-, TNF-α-, and IFN-γ-induced CX3CL1 production by FTDCs.

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Ssc-novel-miR-106-5p reduces lipopolysaccharide-induced inflammatory response in porcine endometrial epithelial cells by inhibiting the expression of the target gene mitogen-activated protein kinase kinase kinase 14 (MAP3K14)

Reproduction Fertility and Development ◽

10.1071/rd19097 ◽

2019 ◽

Vol 31 (10) ◽

pp. 1616

Author(s):

Yu Lian ◽

Yu Hu ◽

Lu Gan ◽

Yuan-Nan Huo ◽

Hong-Yan Luo ◽

...

Keyword(s):

Protein Kinase ◽

Epithelial Cells ◽

Target Gene ◽

Mitogen Activated Protein Kinase ◽

Luciferase Reporter ◽

Nuclear Factor ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Endometrial Epithelial Cells ◽

Protein Kinase Kinase

As an important gram-negative bacterial outer membrane component, lipopolysaccharide (LPS) plays an important role in bacterial-induced endometritis in sows. However, how LPS induces endometritis is unclear. We stimulated sow endometrial epithelial cells (EECs) with LPS and detected cell viability and tumour necrosis factor-α (TNF-α) and interleukin-1 (IL-1) secretion. LPS affected EEC viability and TNF-α and IL-1 secretion in a dose-dependent manner. LPS induced differential expression in 10 of 393 miRNAs in the EECs (downregulated, nine; upregulated, one). MicroRNA (miRNA) high-throughput sequencing of the LPS-induced EECs plus bioinformatics analysis and the dual-luciferase reporter system revealed a novel miRNA target gene: mitogen-activated protein kinase kinase kinase 14 (MAP3K14). Ssc-novel-miR-106-5p mimic, inhibitor and the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation inhibitor Bay11–7085 were used to detect EEC nuclear factor-κB phosphorylation levels (p-NF-κB) and TNF-α and IL-1 secretion. MiR-106-5p mimic downregulated MAP3K14 mRNA and protein expression levels, inhibited p-NF-κB levels and decreased IL-1 and TNF-α secretion, whereas miR-106-5p inhibitor had the opposite effect. Bay11–7085 inhibited p-NF-κB expression and TNF-α and IL-1 secretion. These results suggest that LPS downregulates ssc-novel-miR-106-5p expression in sow EECs to increase MAP3K14 expression, which increases p-NF-κB to promote IL-1 and TNF-α secretion.

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Cocoa polyphenols suppress TNF-α-induced vascular endothelial growth factor expression by inhibiting phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase kinase-1 (MEK1) activities in mouse epidermal cells

British Journal Of Nutrition ◽

10.1017/s0007114510001704 ◽

2010 ◽

Vol 104 (7) ◽

pp. 957-964 ◽

Cited By ~ 33

Author(s):

Jong-Eun Kim ◽

Joe Eun Son ◽

Sung Keun Jung ◽

Nam Joo Kang ◽

Chang Yong Lee ◽

...

Keyword(s):

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Vascular Endothelial ◽

Vegf Expression ◽

Ribosomal Protein S6 ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Phosphoinositide 3 Kinase ◽

Endothelial Growth Factor ◽

Protein Kinase Kinase

Cocoa polyphenols have antioxidant and anti-inflammatory effects. TNF-α is a pro-inflammatory cytokine that has a vital role in the pathogenesis of inflammatory diseases such as cancer and psoriasis. Vascular endothelial growth factor (VEGF) expression is associated with tumorigenesis, CVD, rheumatoid arthritis and psoriasis. We tested whether cocoa polyphenol extract (CPE) inhibited TNF-α-induced VEGF expression in promotion-sensitive JB6 mouse epidermal cells. CPE significantly inhibited TNF-α-induced up-regulation of VEGF via reducing TNF-α-induced activation of the nuclear transcription factors activator protein-1 (AP-1) and NF-κB, which are key regulators of VEGF expression. CPE also inhibited TNF-α-induced phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinase. CPE blocked activation of their downstream kinases, p70 kDa ribosomal protein S6 kinase and p90 kDa ribosomal protein S6 kinase. CPE suppressed phosphoinositide 3-kinase (PI3K) activity via binding PI3K directly. CPE did not affect TNF-α-induced phosphorylation of mitogen-activated protein kinase kinase-1 (MEK1) but suppressed TNF-α-induced MEK1 activity. Collectively, these results indicate that CPE reduced TNF-α-induced up-regulation of VEGF by directly inhibiting PI3K and MEK1 activities, which may contribute to its chemopreventive potential.

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A novel role for reciprocal CD30-CD30L signaling in the cross-talk between natural killer and dendritic cells

Biological Chemistry ◽

10.1515/bc-2011-213 ◽

2012 ◽

Vol 393 (1-2) ◽

pp. 101-106 ◽

Cited By ~ 12

Author(s):

Vijaya Lakshmi Simhadri ◽

Hinrich P. Hansen ◽

Venkateswara R. Simhadri ◽

Katrin S. Reiners ◽

Martina Bessler ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Nk Cells ◽

Natural Killer ◽

Cross Talk ◽

Mitogen Activated Protein Kinase ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Ifn Γ ◽

The Cross

Abstract The interplay between dendritic cells (DCs) and natural killer (NK) cells directs adaptive immune responses. The molecular basis of the cross-talk is largely undefined. Here, we provide evidence for a contribution of CD30 (TNFRSF8) and its ligand CD30L (TNFSF8) expressed on NK cells and DCs, respectively. We demonstrate that CD30-mediated engagement of CD30L induced cytokine secretion from immature DCs via the mitogen-activated protein kinase pathway. Moreover, CD30L engagement promoted differentiation to mature DCs. On the contrary, the engagement of CD30 on NK cells resulted in an NF-κB-dependent release of TNF-α/IFN-γ. These data uncover a novel and unexpected role for CD30/CD30L that contributes to proinflammatory immune responses.

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Coordinate Regulation of IκB Kinases by Mitogen-Activated Protein Kinase Kinase Kinase 1 and NF-κB-Inducing Kinase

Molecular and Cellular Biology ◽

10.1128/mcb.18.12.7336 ◽

1998 ◽

Vol 18 (12) ◽

pp. 7336-7343 ◽

Cited By ~ 181

Author(s):

Shino Nemoto ◽

Joseph A. DiDonato ◽

Anning Lin

Keyword(s):

Protein Kinase ◽

Interleukin 1 ◽

Dominant Negative ◽

Mitogen Activated Protein Kinase ◽

Dominant Negative Mutant ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Ikk Complex ◽

Mitogen Activated Protein ◽

Protein Kinase Kinase

ABSTRACT IκB kinases (IKKα and IKKβ) are key components of the IKK complex that mediates activation of the transcription factor NF-κB in response to extracellular stimuli such as inflammatory cytokines, viral and bacterial infection, and UV irradiation. Although NF-κB-inducing kinase (NIK) interacts with and activates the IKKs, the upstream kinases for the IKKs still remain obscure. We identified mitogen-activated protein kinase kinase kinase 1 (MEKK1) as an immediate upstream kinase of the IKK complex. MEKK1 is activated by tumor necrosis factor alpha (TNF-α) and interleukin-1 and can potentiate the stimulatory effect of TNF-α on IKK and NF-κB activation. The dominant negative mutant of MEKK1, on the other hand, partially blocks activation of IKK by TNF-α. MEKK1 interacts with and stimulates the activities of both IKKα and IKKβ in transfected HeLa and COS-1 cells and directly phosphorylates the IKKs in vitro. Furthermore, MEKK1 appears to act in parallel to NIK, leading to synergistic activation of the IKK complex. The formation of the MEKK1-IKK complex versus the NIK-IKK complex may provide a molecular basis for regulation of the IKK complex by various extracellular signals.

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