Lipopolysaccharide inhibits GPR120 expression in macrophages via Toll‐like receptor 4 and p38 MAPK activation

2019 ◽  
Vol 44 (1) ◽  
pp. 89-97 ◽  
Author(s):  
Yan‐Yan Zhao ◽  
Hui Fu ◽  
Xiang‐Yan Liang ◽  
Bi‐Lin Zhang ◽  
Lan‐Lan Wei ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Mapk Activation

scholarly journals ADAM17-Mediated Ectodomain Shedding of Toll-Like Receptor 4 as a Negative Feedback Regulation in Lipopolysaccharide-Activated Aortic Endothelial Cells

2018 ◽  
Vol 45 (5) ◽  
pp. 1851-1862 ◽  
Author(s):  
Won Seok Yang ◽  
Jin Ju Kim ◽  
Mee Jeong Lee ◽  
Eun Kyoung Lee ◽  
Su-Kil Park
Keyword(s):  
Endothelial Cells ◽  
P38 Mapk ◽  
Ectodomain Shedding ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Toll Like Receptor 4 ◽  
Negative Feedback Regulation ◽  
Mapk Activation ◽  
Aortic Endothelial Cells ◽  
Aortic Endothelial

Background/Aims: Lipopolysaccharide (LPS)-activated monocytes/macrophages develop endotoxin tolerance in part by reducing cell surface toll-like receptor 4 (TLR4) through cluster of differentiation 14 (CD14)-dependent endocytosis. In case of endothelial cells, CD14 is expressed in low copy numbers as compared with monocytes/macrophages. Thus, we explored how endothelial cells regulate TLR4 expression after LPS stimulation. Methods: Cultured human aortic endothelial cells (HAECs) were treated with LPS. TLR4 expression was analyzed by Western blot analysis and immunofluorescence staining. A disintegrin and metalloprotease 17 (ADAM17) activity was measured using a fluorescent substrate. Results: TLR4 in cell lysate began to decrease within 30 min of LPS treatment with a maximal reduction at 2 h, and it was accompanied by an increase of N-terminal fragment of TLR4 in culture supernatant, indicating ectodomain shedding of the receptor. LPS activated p38 mitogen-activated protein kinase (p38 MAPK) and ADAM17, while LPS-induced ADAM17 activation was inhibited by SB203580, a p38 MAPK inhibitor. LPS-induced ectodomain shedding of TLR4 was attenuated by siRNA depletion of ADAM17 as well as TAPI-2 (an inhibitor of ADAM family) and SB203580. LPS pretreatment resulted in a blunted response of p38 MAPK activation to further LPS stimulation. In the cells depleted of ADAM17, LPS-induced p38 MAPK activation was prolonged and LPS-induced intercellular adhesion molecule-1 expression was potentiated. Conclusion: HAECs respond to LPS by rapid shedding of the ectodomain of TLR4 and thereby reduce the responsiveness to subsequent LPS exposure. ADAM17, downstream of p38 MAPK, is implicated in the ectodomain cleavage of TLR4.

INJURY SELECTIVELY AUGMENTS TOLL-LIKE RECEPTOR 4 INDUCED P38 MAPK ACTIVATION.

Shock ◽  
2004 ◽  
Vol 21 ◽  
pp. 79-80
Author(s):  
Adrian A. Maung ◽  
Marissa L. Miller ◽  
John A. Mannick ◽  
James A. Lederer
Keyword(s):  
P38 Mapk ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Mapk Activation

Atorvastatin suppresses LPS-induced rapid upregulation of Toll-like receptor 4 and its signaling pathway in endothelial cells

2011 ◽  
Vol 300 (5) ◽  
pp. H1743-H1752 ◽  
Author(s):  
Ying Wang ◽  
Ming Xiang Zhang ◽  
Xiao Meng ◽  
Fu Qiang Liu ◽  
Guang Sheng Yu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mrna Expression ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Umbilical Vein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Mapk Phosphorylation ◽  
Tlr4 Mrna

In the present study, we tested our hypothesis that atorvastatin exerts its anti-inflammation effect via suppressing LPS-induced rapid upregulation of Toll-like receptor 4 (TLR4) mRNA and its downstream p38, ERK, and NF-κB signaling pathways in human umbilical-vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs). TLR4 mRNA expression and its downstream kinase activities induced by LPS alone or atorvastatin + LPS in endothelial cells were quantified using quantitative real-time PCR and enzyme-linked immunosorbent assay. Preincubation of LPS-stimulated endothelial cells with TLR4 siRNA was conducted to identify the target of the anti-inflammatory effects of atorvastatin. Atorvastatin incubation resulted in the reduction of LPS-induced TLR4 mRNA expression, ERK1/2 and P38 MAPK phosphorylation, and NF-κB binding activity. Pretreatment with MEK/ERK1/2 inhibitor PD98059 attenuated atorvastatin + LPS-induced NF-κB activity but had no effect on P38 MAPK phosphorylation. In contrast, pretreatment with P38 MAPK inhibitor SB203580 resulted in upregulation of atorvastatin + LPS-induced ERK1/2 phosphorylation but had no significant effects on NF-κB activity. On the other hand, blocking NF-κB with SN50 produced no effects on atorvastatin + LPS-induced ERK1/2 and P38 MAPK phosphorylation. Moreover, TLR4 gene silencing produced the same effects as the atorvastatin treatment. In conclusion, atorvastatin downregulated TLR4 mRNA expression by two distinct signaling pathways. First, atorvastatin stabilized Iκ-Bα, which directly inhibited NF-κB activation. Second, atorvastatin inactivated ERK phosphorylation, which indirectly inhibited NF-κB activation. Suppression of p38 MAPK by atorvastatin upregulates ERK but exerts no effect on NF-κB.

scholarly journals A Novel Role of Numb as A Regulator of Pro-inflammatory Cytokine Production in Macrophages in Response to Toll-like Receptor 4

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Patipark Kueanjinda ◽  
Sittiruk Roytrakul ◽  
Tanapat Palaga
Keyword(s):  
Notch Signaling ◽  
P38 Mapk ◽  
Inflammatory Responses ◽  
Notch Signaling Pathway ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Murine Bone Marrow

Abstract Activation of macrophages triggers the release of pro-inflammatory cytokines leading to inflammation. Numb is a negative regulator of Notch signaling, but the role of Numb in macrophages is not fully understood. In this study, the role of Numb as a regulator of inflammatory responses in macrophages was investigated. Murine bone marrow-derived macrophages, in which expression of Numb was silenced, secreted significantly less TNFα, IL-6 and IL-12 and more IL-10 upon activation by lipopolysaccharide (LPS), a ligand for Toll-like receptor 4 (TLR4), despite increased Notch signaling. The Tnfα mRNA levels both in Numb-deficient and wild-type macrophages were not significantly different, unlike those of Il6 and Il12-p40. In Numb-deficient macrophages, the Tnfα mRNAs were degraded at faster rate, compared to those in control macrophages. Activation of p38 MAPK and NF-κΒ p65 were compromised in activated Numb deficient macrophages. Numb was found to interact with the E3 ubiquitin ligase, Itch, which reportedly regulates p38 MAPK. In addition, blocking the Notch signaling pathway in activated, Numb-deficient macrophages did not further reduce TNFα levels, suggesting a Notch-independent role for Numb. A proteomics approach revealed a novel funciton for Numb in regulating complex signaling cascades downstream of TLRs, partially involving Akt/NF-κB p65/p38 MAPK in macrophages.

scholarly journals Herbal melanin induces interleukin‑1β secretion and production by human THP‑1 monocytes via Toll‑like receptor 2 and p38 MAPK activation

2021 ◽  
Vol 22 (4) ◽  
Author(s):  
Adila El‑Obeid ◽  
Wesam Yahya ◽  
Bader Almuzzaini ◽  
Abeer Tuwaijri ◽  
Maria Najdi ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Interleukin 1Β ◽  
Toll Like Receptor ◽  
Mapk Activation ◽  
Toll Like Receptor 2

scholarly journals Macrophage glucocorticoid receptors regulate Toll-like receptor 4–mediated inflammatory responses by selective inhibition of p38 MAP kinase

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4313-4319 ◽  
Author(s):  
Sandip Bhattacharyya ◽  
Diane E. Brown ◽  
Judson A. Brewer ◽  
Sherri K. Vogt ◽  
Louis J. Muglia
Keyword(s):  
Map Kinase ◽  
P38 Mapk ◽  
Glucocorticoid Receptors ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Specific Inhibitor ◽  
P38 Map Kinase ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Map Kinase Phosphatase

Abstract To explore the role of glucocorticoids in regulation of kinase pathways during innate immune responses, we generated mice with conditional deletion of glucocorticoid receptor (GR) in macrophages (MGRKO). Activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) caused greater mortality and cytokine production in MGRKO mice than in controls. Ex vivo, treatment with dexamethasone (Dex) markedly inhibited LPS-mediated induction of inflammatory genes in control but not GR-deficient macrophages. We show that Dex inhibits p38 MAPK, but not PI3K/Akt, ERK, or JNK, in control macrophages. Associated with p38 inhibition, Dex induced MAP kinase phosphatase-1 (MKP-1) in control, but not MGRKO, macrophages. Consistent with the ex vivo studies, treatment with a p38 MAPK–specific inhibitor resulted in rescue of MGRKO mice from LPS-induced lethality. Taken together, we identify p38 MAPK and its downstream targets as essential for GR-mediated immunosuppression in macrophages.

scholarly journals Toll-Like Receptor 4-Mediated Activation of p38 Mitogen-Activated Protein Kinase Is a Determinant of Respiratory Virus Entry and Tropism

2010 ◽  
Vol 84 (21) ◽  
pp. 11359-11373 ◽  
Author(s):  
David Marchant ◽  
Gurpreet K. Singhera ◽  
Soraya Utokaparch ◽  
Tillie L. Hackett ◽  
John H. Boyd ◽  
...  
Keyword(s):  
Influenza Virus ◽  
P38 Mapk ◽  
Respiratory Virus ◽  
Respiratory Viruses ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Virus Infections ◽  
Toll Like Receptor 4 ◽  
Mitogen Activated Protein ◽  
Respiratory Virus Infections

ABSTRACT Respiratory viruses exert a heavy toll of morbidity and mortality worldwide. Despite this burden there are few specific treatments available for respiratory virus infections. Since many viruses utilize host cell enzymatic machinery such as protein kinases for replication, we determined whether pharmacological inhibition of kinases could, in principle, be used as a broad antiviral strategy for common human respiratory virus infections. A panel of green fluorescent protein (GFP)-expressing recombinant respiratory viruses, including an isolate of H1N1 influenza virus (H1N1/Weiss/43), was used to represent a broad range of virus families responsible for common respiratory infections (Adenoviridae, Paramyxoviridae, Picornaviridae, and Orthomyxoviridae). Kinase inhibitors were screened in a high-throughput assay that detected virus infection in human airway epithelial cells (1HAEo-) using a fluorescent plate reader. Inhibition of p38 mitogen-activated protein kinase (MAPK) signaling was able to significantly inhibit replication by all viruses tested. Therefore, the pathways involved in virus-mediated p38 and extracellular signal-regulated kinase (ERK) MAPK activation were investigated using bronchial epithelial cells and primary fibroblasts derived from MyD88 knockout mouse lungs. Influenza virus, which activated p38 MAPK to approximately 10-fold-greater levels than did respiratory syncytial virus (RSV) in 1HAEo- cells, was internalized about 8-fold faster and more completely than RSV. We show for the first time that p38 MAPK is a determinant of virus infection that is dependent upon MyD88 expression and Toll-like receptor 4 (TLR4) ligation. Imaging of virus-TLR4 interactions showed significant clustering of TLR4 at the site of virus-cell interaction, triggering phosphorylation of downstream targets of p38 MAPK, suggesting the need for a signaling receptor to activate virus internalization.

scholarly journals The p38 Mitogen-Activated Protein Kinase Signaling Pathway Is Coupled to Toll-Like Receptor 5 To Mediate Gene Regulation in Response to Pseudomonas aeruginosa Infection in Human Airway Epithelial Cells

2007 ◽  
Vol 75 (12) ◽  
pp. 5985-5992 ◽  
Author(s):  
Zhe Zhang ◽  
William Reenstra ◽  
Daniel J. Weiner ◽  
Jean-Pierre Louboutin ◽  
James M. Wilson
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Gene Regulation ◽  
P38 Mapk ◽  
Airway Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Airway Epithelial ◽  
Toll Like Receptor ◽  
Mapk Activation ◽  
Mitogen Activated Protein ◽  
Toll Like Receptor 5

ABSTRACT In this study, we show that stimulation of human airway epithelial cells (HAECs) by Pseudomonas aeruginosa strain PAO1 induces time- and dose-dependent activation of p38 mitogen-activated protein kinase (MAPK). Activated p38 MAPK stayed in the cytoplasm instead of translocating to the nucleus, as shown by cellular fractionation. p38 MAPK was activated when HAECs were incubated with P. aeruginosa strain PAK and Burkholderia cepacia, while little activation was observed with the isogenic flagellin-free strains PAK/fliC and B. cepacia BC/fliC. The presence of Toll-like receptor 5 (TLR5) in 293 cells mediated PAO1-dependent activation of p38 MAPK, and in HAECs p38 MAPK activation was blocked by the overexpression of a dominant negative TLR5. Two inhibitors of p38 MAPK, SB202190 and SB203580, significantly attenuated PAO1-dependent expression of an NF-κB-dependent luciferase reporter gene, suggesting that p38 MAPK activation is required for full activation of NF-κB-dependent signaling. Microarray analysis of NF-κB target genes revealed up-regulation of multiple genes by PAO1 in HAECs. Reverse transcription-PCR and protein expression analysis were used to show that up-regulation of NF-κB-dependent genes induced by PAO1, such as the genes encoding Cox-2 and interleukin-8, was attenuated by SB203580. These results demonstrate a role for p38 MAPK signaling in gene regulation in response to P. aeruginosa via TLR5.

Pneumolysin-induced CXCL8 production by nasopharyngeal epithelial cells is dependent on calcium flux and MAPK activation via Toll-like receptor 4

2011 ◽  
Vol 13 (1) ◽  
pp. 65-75 ◽  
Author(s):  
Semih Dogan ◽  
Qibo Zhang ◽  
Alison C. Pridmore ◽  
Timothy J. Mitchell ◽  
Adam Finn ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Calcium Flux ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Mapk Activation ◽  
Nasopharyngeal Epithelial
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