TWEAK/Fn14 interaction induces proliferation and migration in human airway smooth muscle cells via activating the NF‐κB pathway

Zhu, Cuimin; Zhang, Leguo; Liu, Zhiming; Li, Chen; Bai, Yajie

doi:10.1002/jcb.26525

Cited by 26 publications

(11 citation statements)

References 25 publications

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“…In addition, like mentioned above with IFN-γ, we used only 2% FCS in culture medium for proliferation assays, which might change the effects of TWEAK from inhibitory to stimulatory. TWEAKs ability to promote proliferation is in line with in vivo results, where TWEAK has been shown to stimulate wound-healing 46,47 . APRIL modestly increased TNF-induced proliferation but not IL-6 or IL-8 production.…”

Section: Discussionsupporting

confidence: 70%

Positive and negative cooperativity of TNF and Interferon-γ in regulating synovial fibroblast function and B cell survival in fibroblast/B cell co-cultures

Lowin

Anssar

Bäuml

et al. 2020

Sci Rep

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Synovial fibroblasts (SF) were reported to produce B cell activating factor (BAFF) in response to stimulation with interferon-γ (IFN-γ) or tumor necrosis factor (TNF). However, the influence of these pro-inflammatory cytokines on other receptors/ligands of the TNF superfamily or associated cytokine receptors in SF has not been investigated yet. Here we show the differential regulation of BAFF (CD257), Fn14 (CD266), TACI (CD267), BAFF-R (CD268), BCMA (CD269), CD40 ligand (CD40L, CD154), IFN-γR (CD119), Leptin receptor (ObR, CD295), VCAM-1 (CD106) and membrane TGF-β in isolated Sf and the impact of ifn-γ/TNF co-incubation on proliferation, IL-6 and IL-8 production. In addition, the impact of differentially stimulated SF on B cell survival in co-cultures was assessed. Surface cytokines and cytokine receptors were detected by flow cytometry. Soluble cytokine receptors and cytokines were quantified by ELISA. Proliferation was assessed by cell titer blue. Murine B cell survival in fibroblast/ B cell co-cultures was determined by annexin V/propidium iodide staining and flow cytometry. IFN-γ together with TNF synergistically and significantly increased the cell surface levels of BAFF, Fn14, TACI, BAFF-R, BCMA, CD40L, ObR and IFN-γR in rheumatoid arthritis SF after 72 h incubation. Soluble BAFF was only induced by IFN-γ and inhibited by TNF. Addition of TWEAK had no influence on proliferation or IL-8 production but decreased TNF-induced IL-6 production, whereas APRIL, BAFF and leptin did not modulate TNF or TNF/IFN-γ-induced proliferation or cytokine production. Proliferation was increased by TNF and further enhanced by the addition of IFN-γ. In co-culture experiments, SF stimulated with TNF/IFN but not TNF or IFN-γ alone increased shedding of VCAM-1 and expression of membrane TGFβ, which was associated with reduced survival of murine B cells. ifn-γ and TNF regulate the expression of TNF family member cytokines and associated receptors. Ligation of IFN-γR and Fn14 under proinflammatory conditions modulated IL-6/IL-8 production and proliferation. In B cell/SF co-cultures, the combination of TNF/IFN reduced B cell survival possibly via enhanced VCAM-1 shedding and/ or increased tGf-β production. ifn-γ is necessary for the observed effects on B cell survival and SF cytokine production and emphasizes its anti-inflammatory role in rheumatoid arthritis. In rheumatoid arthritis (RA), interferon-γ (IFN-γ) levels are increased in synovial fluid and concomitantly, synovial fluid mononuclear cells show increased IFN-γ mRNA levels 1,2. IFN-γ has a dual role in chronic inflammation since it does increase the presentation of antigens via induction of MHC class II molecules in synovial fibroblasts

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Section: Discussionsupporting

confidence: 70%

Positive and negative cooperativity of TNF and Interferon-γ in regulating synovial fibroblast function and B cell survival in fibroblast/B cell co-cultures

Lowin

Anssar

Bäuml

et al. 2020

Sci Rep

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“…It has also been shown that, SP-A is unable to activate NF-kB in response to O 3 as assessed by the lack of changes in the nuclear p65 subunit and the cytoplasmic IkBa levels as it would have been expected in the classical NF-kB pathway (87). Moreover, it has been shown that decreased levels of MTDH expression attenuate NF-kB signaling (88) and that TNFSF12 regulates NF-kB activity (89). Upregulation of TNFSF12 and MTDH as it occurs in co-ex males in the current study may alter NF-kB signaling, enhance its translocation to the nucleus to facilitate the transcription of pro-inflammatory genes in co-ex males but not in females.…”

Section: Discussionmentioning

confidence: 99%

Differential Impact of Co-expressed SP-A1/SP-A2 Protein on AM miRNome; Sex Differences

et al. 2019

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In humans there are two surfactant protein A (SP-A) functional genes SFTPA1 and SFTPA2 encoding innate immune molecules, SP-A1 and SP-A2, respectively, with numerous genetic variants each. SP-A interacts and regulates many of the functions of alveolar macrophages (AM). It is shown that SP-A variants differ in their ability to regulate the AM miRNome in response to oxidative stress (OxS). Because humans have both SP-A gene products, we were interested to determine the combined effect of co-expressed SP-A1/SP-A2 (co-ex) in response to ozone (O 3 ) induced OxS on AM miRNome. Human transgenic (hTG) mice, carrying both SP-A1/SP-A2 (6A 2 /1A 0 , co-ex) and SP-A- KO were utilized. The hTG and KO mice were exposed to filtered air (FA) or O 3 and miRNA levels were measured after AM isolation with or without normalization to KO. We found: (i) The AM miRNome of co-ex males and females in response to OxS to be largely downregulated after normalization to KO, but after Bonferroni multiple comparison analysis only in females the AM miRNome remained significantly different compared to control (FA); (ii) The targets of the significantly changed miRNAs were downregulated in females and upregulated in males; (iii) Several of the validated mRNA targets were involved in pro-inflammatory response, anti-apoptosis, cell cycle, cellular growth and proliferation; (iv) The AM of SP-A2 male, shown, previously to have major effect on the male AM miRNome in response to OxS, shared similarities with the co-ex, namely in pathways involved in the pro-inflammatory response and anti-apoptosis but also exhibited differences with the cell-cycle, growth, and proliferation pathway being involved in co-ex and ROS homeostasis in SP-A2 male. We speculate that the presence of both gene products vs. single gene products differentially impact the AM responses in males and females in response to OxS.

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“…Human tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a protein expressed in various cell types, including inflammatory cells, such as monocytes, macrophages, dendritic cells, T cells, and NK cells; acting through its highly inducible receptor, named fibroblast growth factor-inducible 14 (Fn14), TWEAK may contribute to the development of airway inflammation and, in particular, potentially stimulate human bronchial epithelial cells to produce proinflammatory IL-8 and granulocyte-macrophage colony-stimulating factor. 157 Kim et al evaluated the airway TWEAK levels in a large population of 230 children with noneosinophilic asthma: sputum TWEAK levels were significantly elevated in children with asthma and higher in children with greater asthma severity and poorer control status; moreover, the authors found a negative correlation between sputum TWEAK levels and the spirometric parameters of bronchial obstruction, supporting the possible association of TWEAK with airway obstruction and remodeling. 158 Thus, the TWEAK/Fn14 axis may also represent a future therapeutic target for limiting airway remodeling in asthma.…”

Section: Biomarkers In Childhood Asthmamentioning

confidence: 99%

Asthma Endotyping and Biomarkers in Childhood Asthma

Licari

Brambilla

Marseglia

et al. 2018

Pediatric Allergy, Immunology, and Pulmonology

129

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Childhood asthma represents a heterogeneous challenging disease, in particular in its severe forms. The identification of different asthma phenotypes has stimulated research in underlying molecular mechanisms, such as the endotypes, and paved the way to the search for related specific biomarkers, which may guide diagnosis, management, and predict response to treatment. A limited number of biomarkers are currently available in clinical practice in the pediatric population, mostly reflecting type 2-high airway inflammation. The identification of biomarkers of childhood asthma is an active area of research that holds a potential great clinical utility and may represent a step forward toward tailored management and therapy: the so-called Precision Medicine. The aim of the present review is to provide an updated overview of asthma endotyping, mostly focusing on novel noninvasive biomarkers in childhood asthma.

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TWEAK/Fn14 interaction induces proliferation and migration in human airway smooth muscle cells via activating the NF‐κB pathway

Cited by 26 publications

References 25 publications

Positive and negative cooperativity of TNF and Interferon-γ in regulating synovial fibroblast function and B cell survival in fibroblast/B cell co-cultures

Positive and negative cooperativity of TNF and Interferon-γ in regulating synovial fibroblast function and B cell survival in fibroblast/B cell co-cultures

Differential Impact of Co-expressed SP-A1/SP-A2 Protein on AM miRNome; Sex Differences

Asthma Endotyping and Biomarkers in Childhood Asthma

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