TNFα-induced airway smooth muscle cell proliferation depends on endothelin receptor signaling, GM-CSF and IL-6

Knobloch, Jürgen; Yanik, Sarah; Körber, Sandra; Stoelben, Erich; Jungck, David; Koch, Andrea

doi:10.1016/j.bcp.2016.07.008

Cited by 21 publications

(12 citation statements)

References 35 publications

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“…It is also used to treat cardiovascular diseases such as hypertension and obesity cardiomyopathy because of the regulatory effect of endothelin on the ET1-ETAR system ( 4 , 5 , 14 , 57 ). A few studies have reported that BQ123 suppresses the ET1-ETAR system-mediated inflammatory cytokine TNFα, preventing inflammation-induced airway smooth muscle hyperplasia and diabetic retinopathy ( 10 , 12 ). BQ123 has also been found to reduce ROS production and TNF-α and IL-6 levels through its effects on the ET1-ETAR system, resulting in enhanced antioxidant defense under high glucose conditions ( 9 ).…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, these results indicate that BQ123 can activate PMN-MDSCs but not M-MDSCs in mice, and that Arg1 is involved in BQ123-induced PMN-MDSC-mediated immunosuppression. Previous studies have reported that the effect of BQ123 on various diseases depends on the ET1-ETAR system (10)(11)(12)14). To better understand the nature of the BQ123-derived PMN-MDSC, we performed additional experiments.…”

Section: Bq123 Promoted Pmn-mdsc Activation In Micementioning

confidence: 99%

“…The ET1/ETAR system blocking with BQ123 may have clinical applications in the treatment of septic shock (9). It has also been reported that BQ123 can reduce the expression of proinflammatory cytokines, including reactive oxygen species (ROS), tumor necrosis factor (TNF)-a, interleukin (IL)-1, and IL-6, by regulating the ET1/ ETAR system (10)(11)(12). BQ123 may also play a role in alleviating chronic airway inflammatory obstructive asthma by reducing fibrocyte differentiation and progression (13).…”

Section: Introductionmentioning

confidence: 99%

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Treatment With Endothelin-A Receptor Antagonist BQ123 Attenuates Acute Inflammation in Mice Through T-Cell-Dependent Polymorphonuclear Myeloid-Derived Suppressor Cell Activation

Chen

Zhang

et al. 2021

Front. Immunol.

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The endothelin-A receptor antagonist BQ123 is an effective treatment agent for hypertension and obese cardiomyopathy. However, the role of BQ123 in controlling acute inflammatory diseases and its underlying mechanisms are not well understood. Here, we showed that BQ123 activated polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in mice and that the IL13/STAT6/Arg1 signaling pathway is involved in this process. Importantly, both treatment with BQ123 and the transfer of BQ123-induced PMN-MDSCs (BQ123-MDSCs) were effective in relieving inflammation, including dextran sulfate sodium (DSS)-induced colitis, papain-induced pneumonia, and concanavalin A (ConA)-induced hepatitis, in mice. The treatment effects were mediated by the attenuation of the inflammation associated with the accumulation of PMN-MDSCs in the colon, lung, and liver. However, concurrent injection of Gr1 agonistic antibody with BQ123 induced PMN-MDSC aggravated the observed acute inflammation. Interestingly, no remission of inflammation was observed in Rag2 knockout mice administered BQ123-MDSCs, but co-injection with CD3+ T cells significantly relieved acute inflammation. In summary, BQ123-induced PMN-MDSCs attenuated acute inflammation in a T cell-dependent manner, providing a novel potential strategy to prevent the occurrence of acute inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Bq123 Promoted Pmn-mdsc Activation In Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Treatment With Endothelin-A Receptor Antagonist BQ123 Attenuates Acute Inflammation in Mice Through T-Cell-Dependent Polymorphonuclear Myeloid-Derived Suppressor Cell Activation

Chen

Zhang

et al. 2021

Front. Immunol.

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“…[18,19] Endothelin-1 is a 21-amino-acid peptide contained a single alpha-helix and two disulfide bridges and has been proven to stimulate cell proliferation in various cells including osteoblasts, fibroblasts, vascular smooth muscle and melanocytes. [20][21][22][23] EDN-1 can also increase VEGF production via EDN-1 receptor and thus play an important role in tissue angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

In vivo and in vitro study of osteogenic potency of endothelin-1 on bone marrow-derived mesenchymal stem cells

Wang

Jiang

et al. 2017

Experimental Cell Research

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“…Human airway smooth muscle cells (HASMCs) have been identified as an important source of COPD-related cytokines and chemokines that link corticosteroid-resistant non-type 2 airway inflammation to remodeling processes [6,13]. This includes endothelin-1 and GM-CSF, both of which are involved in the regulation of HASMC proliferation and, therefore, contribute to the increase in airway smooth muscle mass, leading to bronchial obstruction [13]. However, the most important cytokine might be IL-8 [6].…”

Section: Introductionmentioning

confidence: 99%

LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD

Knobloch

Jungck

Kronsbein

et al. 2019

JCM

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Airway inflammation in chronic obstructive pulmonary disease (COPD) is partially insensitive/resistant to inhaled corticosteroids (ICS). ICS plus bronchodilator therapy has been discussed for COPD phenotypes with frequent exacerbations and participation of corticosteroid-sensitive type 2/eosinophilic inflammation. Neutralization of non-type 2/IL-8-associated airway inflammation by reversion of its corticosteroid-resistance might be a future strategy for other phenotypes. Human airway smooth muscle cells (HASMCs) produce corticosteroid-insensitive IL-8 in response to TNFα or LPS in stable disease stages or bacteria-induced exacerbations, respectively. p38-mitogen-activated-protein-kinases (p38MAPKs) are alternative therapeutic targets. Hypothesis: long-acting-β2-agonists (LABAs) reverse the corticosteroid-insensitivity of IL-8 by p38MAPK inhibition in HASMCs. Cultivated HASMCs from COPD subjects were pre-incubated with formoterol, salmeterol, fluticasone-propionate, BIRB796 (p38MAPKα, -γ, -δ inhibitor), and/or SB203580 (p38MAPKα and -β inhibitor) before stimulation with TNFα or LPS. IL-8 and MAPK-activities were measured by ELISA. Formoterol, salmeterol, and fluticasone did not or hardly reduced TNFα- or LPS-induced IL-8. BIRB796 and SB203580 reduced TNFα-induced IL-8. SB203580 reduced LPS-induced IL-8. Fluticasone/formoterol, fluticasone/salmeterol, and fluticasone/BIRB796, but not fluticasone/SB203580 combinations, reduced TNFα-induced IL-8 stronger than single treatments. All combinations including fluticasone/SB203580 reduced LPS-induced IL-8 stronger than single treatments. TNFα induced p38MAPKα and -γ activity. LPS induced p38MAPKα activity. Formoterol reduced TNFα-induced p38MAPKγ and LPS-induced p38MAPKα activity. LABAs reverse the corticosteroid-insensitivity of IL-8 in airway smooth muscles via p38MAPKγ in stable disease and via p38MAPKα in exacerbations. Our pre-clinical data indicate a utility for also adding ICS in non-type 2 inflammatory COPD phenotypes to bronchodilator therapy. Depending on phenotype and disease stage, isoform-specific p38MAPK blockers might also reverse corticosteroid-resistance in COPD.

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TNFα-induced airway smooth muscle cell proliferation depends on endothelin receptor signaling, GM-CSF and IL-6

Cited by 21 publications

References 35 publications

Treatment With Endothelin-A Receptor Antagonist BQ123 Attenuates Acute Inflammation in Mice Through T-Cell-Dependent Polymorphonuclear Myeloid-Derived Suppressor Cell Activation

Treatment With Endothelin-A Receptor Antagonist BQ123 Attenuates Acute Inflammation in Mice Through T-Cell-Dependent Polymorphonuclear Myeloid-Derived Suppressor Cell Activation

In vivo and in vitro study of osteogenic potency of endothelin-1 on bone marrow-derived mesenchymal stem cells

LABAs and p38MAPK Inhibitors Reverse the Corticosteroid-Insensitivity of IL-8 in Airway Smooth Muscle Cells of COPD

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