Endothelial Dysfunction in Tristetraprolin-deficient Mice Is Not Caused by Enhanced Tumor Necrosis Factor-α Expression

Bollmann, Franziska; Wu, Zijian; Oelze, Matthias; Siuda, Daniel; Xia, Ning; Henke, J; Daiber, Andreas; Li, Huige; Stumpo, Deborah J.; Blackshear, Perry J.; Kleinert, Hartmut; Pautz, Andrea

doi:10.1074/jbc.m114.566984

Cited by 19 publications

(18 citation statements)

References 71 publications

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“…TTP is found at sites of inflammation, and is colocalized with active p38 MAPK (Ross et al, 2017). It is implied that the strong expression of TTP protein may function as a suppressor of inflammation by down-regulating inflammatory cytokines, chemokines, as well as adhesion molecules (Bollmann et al, 2014). Based on the present work, TTP is insensitive to hypoxic stress, but it increased to other severe insults such as DOR inhibition and TNF-α exposure.…”

Section: Discussionsupporting

confidence: 58%

The δ-Opioid Receptor Differentially Regulates MAPKs and Anti-inflammatory Cytokines in Rat Kidney Epithelial Cells Under Hypoxia

Luo

Song

et al. 2020

Front. Physiol.

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Hypoxic injury is one of the most important factors in progressive kidney disorders. Since we have found that δ-opioid receptor (DOR) is neuroprotective against hypoxic stress through a differential regulation of mitogen-activated protein kinases (MAPKs) and anti-inflammatory cytokines, we asked if DOR that is highly expressed in the kidney can modulate renal MAPKs and anti-inflammatory cytokines under hypoxia. We exposed cultured rat kidney epithelial cells (NRK-52E) to prolonged hypoxia (1% O 2) with applications of specific DOR agonist or/and antagonist to examine if DOR affects hypoxia-induced changes in MAPKs and anti-inflammatory cytokines. The results showed that endogenous DOR expression remained unchanged under hypoxia, while DOR activation with UFP-512 (a specific DOR agonist) reversed the hypoxia-induced up-regulation of ERK1/2 and p38 phosphorylation. DOR inhibition with naltrindole had no appreciable effect on the hypoxia-induced changes in ERK1/2 phosphorylation, but increased p38 phosphorylation. DOR inhibition with naltrindole attenuated the effects of DOR activation on the changes in ERK1/2 and p38 phosphorylation in hypoxia. Moreover, DOR activation/inhibition differentially affected the expression of transcriptional repressor B-cell lymphoma 6 (Bcl-6), anti-inflammatory cytokines tristetraprolin (TTP), and interleukin-10 (IL-10). Taken together, our novel data suggest that DOR activation differentially regulates ERK1/2, p38, Bcl-6, TTP, and IL-10 in the renal cells under hypoxia.

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Section: Discussionsupporting

confidence: 58%

The δ-Opioid Receptor Differentially Regulates MAPKs and Anti-inflammatory Cytokines in Rat Kidney Epithelial Cells Under Hypoxia

Luo

Song

et al. 2020

Front. Physiol.

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“…Disease progression in ihTNF-tg S100A9 -/mice was significantly aggravated compared with that in ihTNF-tg mice, as shown by loss of body weight and grip strength as well as increased paw swelling. None of the control mice developed any TTP KO (24,25), we crossed S100A9 -/mice with the ihTNF-tg mouse strain, which displays features of psoriatic arthritis 3 to 6 weeks after TNF-α induction (26). Expression of human TNF-α was induced in adult mice by doxycycline (dox) for up to Figure 2.…”

Section: Resultsmentioning

confidence: 99%

Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation

Vogl¹,

Stratis²,

Wixler³

et al. 2018

Journal of Clinical Investigation

184

187

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Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/S100A9)2 tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-α-driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9-/- mice with 2 independent TNF-α-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects.

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“…The availability of HuR binding sites is increased following adenosine-to-inosine RNA editing, a process that is promoted both by inflammatory stimuli [172] and hypoxia [173], providing an additional mechanism for the regulation of CTSS by both of these stimuli. TTP also regulates pro-inflammatory responses through the destabilization of mRNA and has a significant anti-inflammatory effect in the airways [174,175]. PP2A, a previously discussed regulator of CTSS expression, enhances TTP destabilization of mRNA providing an additional mechanism for PP2Aassociated regulation of CTSS [176].…”

Section: Regulation Of Expressionmentioning

confidence: 97%

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

et al. 2020

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Dysregulated expression and activity of cathepsin S (CTSS), a lysosomal protease and a member of the cysteine cathepsin protease family, is linked to the pathogenesis of multiple diseases, including a number of conditions affecting the lungs. Extracellular CTSS has potent elastase activity and by processing cytokines and host defense proteins, it also plays a role in the regulation of inflammation. CTSS has also been linked to G-coupled protein receptor activation and possesses an important intracellular role in major histocompatibility complex class II antigen presentation. Modulated CTSS activity is also associated with pulmonary disease comorbidities, such as cancer, cardiovascular disease, and diabetes. CTSS is expressed in a wide variety of immune cells and is biologically active at neutral pH. Herein, we review the significance of CTSS signaling in pulmonary diseases and associated comorbidities. We also discuss CTSS as a plausible therapeutic target and describe recent and current clinical trials examining CTSS inhibition as a means for treatment. Proteases in pulmonary diseases Research in the last 60 years has demonstrated that proteases are critical contributors to pulmonary disease pathophysiology. Initially known as protein-degrading enzymes with a restricted spectrum of substrates, recent studies have revealed that the diversity of protease substrates and biological effects triggered by their processing is vast [1, 2]. Proteases are primarily known for their matrix degradation capabilities, but also play significant roles in other biological mechanisms such as angiogenesis, growth factor bioavailability, cytokine processing, receptor shedding and activation, as well as cellular processes including migration, proliferation, invasion, and survival [3]. Importantly, protease activity requires tight regulation, and disruption of the close interplay between proteases, substrates and inhibitors may contribute to the pathogenesis and progression of a variety of pulmonary diseases, including muco-inflammatory diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), as well as infection [4]. In pulmonary diseases with a high neutrophil burden such as CF, a protease:antiprotease imbalance is frequently observed. The activity of proteases such as neutrophil elastase (NE) in the respiratory tract is regulated by antiproteases, such as α1-antitrypsin (A1AT) [5], secretory leukoprotease inhibitor (SLPI) [6] and elafin [7]. However, in diseases like CF, the antiproteases are overburdened by their cognate proteases and this imbalance can result in chronic airway inflammation, decreased mucociliary clearance, mucus obstruction, extracellular matrix (ECM) remodeling, increased susceptibility to infection and impaired immune responses [8].

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Endothelial Dysfunction in Tristetraprolin-deficient Mice Is Not Caused by Enhanced Tumor Necrosis Factor-α Expression

Cited by 19 publications

References 71 publications

The δ-Opioid Receptor Differentially Regulates MAPKs and Anti-inflammatory Cytokines in Rat Kidney Epithelial Cells Under Hypoxia

The δ-Opioid Receptor Differentially Regulates MAPKs and Anti-inflammatory Cytokines in Rat Kidney Epithelial Cells Under Hypoxia

Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

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