GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes

Sadeghi, Kambis; Wisgrill, Lukas; Wessely, Isabelle; Diesner, Susanne C.; Schüller, Simone; Dürr, Celia; Heinle, Armando; Sachet, Monika; Pollak, Arnold; Förster-Waldl, Elisabeth; Spittler, Andreas

doi:10.1371/journal.pone.0162667

Cited by 22 publications

(17 citation statements)

References 31 publications

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“…The mechanisms involved in downregulation or upregulation of TLRs are far from being fully understood. Authors have shown the involvement of transcription factors, miRNAs, cytokines, and proteins ( Sadeghi et al, 2016 ; Liu et al, 2017 ), but so far, it is not clear how a highly endotoxic molecule receptor is upregulated in the presence of LPS. Both TLR-2 and TLR-4 receptors can activate the MyD88 pathway, which involves the early activation of NF-κB.…”

Section: Discussionmentioning

confidence: 99%

Physical Exercise Exacerbates Acute Kidney Injury Induced by LPS via Toll-Like Receptor 4

et al. 2020

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Introduction: Lipopolysaccharide (LPS) is a systemic response-triggering endotoxin, which has the kidney as one of its first targets, thus causing acute injuries to this organ. Physical exercise is capable of promoting physiological alterations and modulating inflammatory responses in the infectious process through multiple parameters, including the toll-like receptor (TLR)-4 pathway, which is the main LPS signaling in sepsis. Additionally, previous studies have shown that physical exercise can be both a protector factor and an aggravating factor for some kidney diseases. This study aims at analyzing whether physical exercise before the induction of LPS endotoxemia can protect kidneys from acute kidney injury. Methods: C57BL/6J male mice, 12 weeks old, were distributed into four groups: (1) sedentary (control, N = 7); (2) sedentary + LPS ( N = 7); (3) trained ( N = 7); and (4) trained + LPS ( N = 7). In the training groups, the animals exercised 5×/week in a treadmill, 60 min/day, for 4 weeks (60% of max. velocity). Sepsis was induced in the training group by the application of a single dose of LPS (5 mg/kg i.p.). Sedentary animals received LPS on the same day, and the non-LPS groups received a saline solution instead. All animals were euthanized 24 h after the administration of LPS or saline. Results: The groups receiving LPS presented a significant increase in serum urea ( p < 0.0001) and creatinine ( p < 0.001) concentration and renal gene expression of inflammatory markers, such as tumor necrosis factor alpha and interleukin-6, as well as TLRs. In addition, LPS promoted a decrease in reduced glutathione. Compared to the sedentary + LPS group, trained + LPS showed overexpression of a gene related to kidney injury (NGAL, p < 0.01) and the protein levels of LPS receptor TLR-4 ( p < 0.01). Trained + LPS animals showed an expansion of the tubulointerstitial space in the kidney ( p < 0.05) and a decrease in the gene expression of hepatic AOAH ( p < 0.01), an enzyme involved in LPS clearance. Conclusion: In contrast to our hypothesis, training was unable to mitigate the renal inflammatory response caused by LPS. On the contrary, it seems to enhance injury by accentuating endotoxin-induced TLR-4 signaling. This effect could be partly due to the modulation of a hepatic enzyme that detoxifies LPS.

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Section: Discussionmentioning

confidence: 99%

Physical Exercise Exacerbates Acute Kidney Injury Induced by LPS via Toll-Like Receptor 4

et al. 2020

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“…Several studies have reported that the immunomodulatory drug pomalidomide down-regulates PU.1, which is one mechanism by which pomalidomide can be used to treat multiple myeloma 17 – 19 . To evaluate the effect of pomalidomide on expression and function of PU.1 in MCs, we treated LAD2 cells with pomalidomide.…”

Section: Resultsmentioning

confidence: 99%

The effect of PU.1 knockdown on gene expression and function of mast cells

Oda

Kasakura

Fujigaki

et al. 2018

Sci Rep

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PU.1 is a hematopoietic cell-specific transcription factor. In the current study, we investigated the role of PU.1 in the gene expression and the function of mouse mast cells (MCs) in vitro and in vivo. When PU.1 siRNA was introduced into bone marrow-derived MCs (BMMCs), IgE-mediated activation was reduced, and the Syk and FcεRIβ mRNA levels were significantly decreased. As the regulatory mechanism of the Syk gene is largely unknown, we performed promoter analysis and found that PU.1 transactivated the Syk promoter through direct binding to a cis-element in the 5′-untranslated region. The involvement of PU.1 in the Syk promoter was also observed in mouse dendritic cells and human MCs, suggesting that the relationship between PU.1 and Syk is common in mammals and in hematopoietic lineages. When antigen was administrated intravenously after the transfusion of siRNA-transfected BMMCs in the mouse footpad, the footpad thickening was significantly suppressed by PU.1 knockdown. Finally, administration of the immunomodulator pomalidomide suppressed passive systemic anaphylaxis of mice. Taken together, these results indicate that PU.1 knockdown might be an efficacious strategy for the prevention of MC-mediated allergic diseases.

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“…TLRs have been shown to be essential for the activation of monocytic cells, and it plays a role in the production of GM-CSF by activating the transcription factor PU.I, which plays a fundamental role in this lineage [82]. In dendritic cells derived from macrophages, TLRs are involved in the synthesis of IL-7, which is an essential interleukin for the maintenance of LT CD8+ [75].…”

Section: Action Mechanism Of Caseins To Induce Hematopoiesis and Immumentioning

confidence: 99%

Caseins as Regulators of Hematopoiesis

Ledesma‐Martínez¹,

Domínguez-Meléndez²,

Aguíñiga-Sánchez³

et al. 2020

Infant Feeding - Breast Versus Formula

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The main physiological role of casein, the main protein component in the milk, is to be a source of amino acids that are required for the growth of the neonate; therefore, casein is considered a highly nutritious protein. Over time, it has been revealed that casein is a protein whose physiological importance reaches levels far superior to the food field, having a wide array of biological activities including antimicrobial activities, facilitating absorption of nutrients, as well as acting as a growth factor and an immune stimulant. Here we analyze how caseins can exert numerous hematopoietic and immunomodulatory actions, their role in granulopoiesis, monocytopoiesis, and lymphopoiesis from the early stages of postnatal development seemingly throughout life, and we wonder if casein could be useful to fight pathogens resistant to antibiotics, inducing a strong immune response in immunosuppressed patients, or even be a prophylactic strategy to prevent infections.

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GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes

Cited by 22 publications

References 31 publications

Physical Exercise Exacerbates Acute Kidney Injury Induced by LPS via Toll-Like Receptor 4

Physical Exercise Exacerbates Acute Kidney Injury Induced by LPS via Toll-Like Receptor 4

The effect of PU.1 knockdown on gene expression and function of mast cells

Caseins as Regulators of Hematopoiesis

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