IL-9 Inhibits Oxidative Burst and TNF-α Release in Lipopolysaccharide-Stimulated Human Monocytes Through TGF-β

Pilette, Charles; Ouadrhiri, Youssef; Snick, Jacques Van; Renauld, Jean‐Christophe; Staquet, P.; Vaerman, Jean‐Pierre; Sibille, Yves

doi:10.4049/jimmunol.168.8.4103

Cited by 57 publications

(45 citation statements)

References 43 publications

(37 reference statements)

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“…Because it is known that monocytes of sepsis patients often show a desensitized phenotype (6,20), we elucidated the underlying mechanism. An attenuated respiratory burst in monocytes/macrophages has been described in response to IL-4, causing LPS-receptor (CD14) and TLR-4 downregulation (24). These transcriptional mechanisms prevent signal transmission provoking cellular activation following LPS binding.…”

Section: Discussionmentioning

confidence: 99%

Activation-Induced Depletion of Protein Kinase Cα Provokes Desensitization of Monocytes/Macrophages in Sepsis

Knethen

Tautenhahn

Lindemann

et al. 2005

The Journal of Immunology

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Sepsis accounts for the majority of fatal casualties in critically ill patients, because extensive research failed to significantly improve appropriate therapy strategies. Thus, understanding molecular mechanisms initiating the septic phenotype is important. Symptoms of septic disease are often associated with monocyte/macrophage desensitization. In this study, we provide evidence that a desensitized cellular phenotype is characterized by an attenuated oxidative burst. Inhibition of the oxidative burst and depletion of protein kinase Cα (PKCα) were correlated in septic patients. To prove that PKCα down-regulation indeed attenuated the oxidative burst, we set up a cell culture model to mimic desensitized monocytes/macrophages. We show that LPS/IFN-γ-treatment of RAW264.7 and U937 cells lowered PKCα expression and went on to confirm these data in primary human monocyte-derived macrophages. To establish a role of PKCα in cellular desensitization, we overexpressed PKCα in RAW264.7 and U937 cells and tested for phorbolester-elicited superoxide formation following LPS/IFN-γ-pretreatment. Inhibition of the oxidative burst, i.e., cellular desensitization, was clearly reversed in cells overexpressing PKCα, pointing to PKCα as the major transmitter in eliciting the oxidative burst in monocytes/macrophages. However, PKCα inactivation by transfecting a catalytically inactive PKCα mutant attenuated superoxide formation. We suggest that depletion of PKCα in monocytes from septic patients contributes to cellular desensitization, giving rise to clinical symptoms of sepsis.

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Section: Discussionmentioning

confidence: 99%

Activation-Induced Depletion of Protein Kinase Cα Provokes Desensitization of Monocytes/Macrophages in Sepsis

Knethen

Tautenhahn

Lindemann

et al. 2005

The Journal of Immunology

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“…Human IL-9 was purified as previously described [7]. LPS from Escherichia coli (serotype O55:B5) was purchased from Difco Laboratories (Detroit, MI, USA), and anti-TGF-b1 mAb (clone TB21, mIgG1) was from Biosource International (Camarillo, CA).…”

Section: Methodsmentioning

confidence: 99%

“…CD14 was detected at the surface of AM, although to a much less extent than on blood monocytes [7]. CD14 expression at the surface of AM was downregulated by preincubation with IL-4 (mean fluorescence intensity (MFI) 42¡4 versus 84¡6, pv0.001).…”

Section: Il-4 But Not Il-9 Inhibits Surface Expression Of Cd14 Lps Rementioning

confidence: 96%

“…The current authors recently showed [7] that IL-9 is capable of inhibiting in vitro human blood monocytes activated by lipopolysaccharide (LPS) for the release of oxygen metabolites and tumour necrosis factor (TNF)-a, similarly to IL-4. This monocyte deactivation by IL-9 probably accounts for the beneficial activity of IL-9 observed in the model of lethal endotoxaemia [8].…”

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confidence: 99%

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Oxidative burst in lipopolysaccharide-activated human alveolar macrophages is inhibited by interleukin-9

Pilette¹,

Ouadrhiri²,

Snick³

et al. 2002

European Respiratory Journal

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Interleukin (IL)-9 is known to regulate many cell types involved in T-helper type 2 responses classically associated with asthma, including B-and T-lymphocytes, mast cells, eosinophils and epithelial cells. In contrast, target cells mediating the effects of IL-9 in the lower respiratory tract remain to be identified. Therefore, the authors evaluated the activity of IL-9 on human alveolar macrophages (AM) from healthy volunteers.AM preincubated with IL-9 before lipopolysaccharide (LPS) stimulation exhibited a decreased oxidative burst, as previously shown with IL-4. The inhibitory effect of IL-9 was abolished by anti-hIL-9Ra monoclonal antibody, and presence of IL-9 receptors on AM was demonstrated by immunofluorescence. Both IL-4 and IL-9 failed to modulate tumour necrosis factor-a, IL-8 and IL-10 release by LPS-stimulated AM. However, several observations suggested that IL-9 and IL-4 act through different mechanisms: 1) interferon-c antagonised the IL-4-but not the IL-9-mediated inhibition of AM oxidative burst; 2) expression of CD14 was downregulated by IL-4 but not by IL-9 and 3) production of tumour growth factor-b by activated AM was potentiated by IL-9 and not by IL-4, and was required for the IL-9-mediated inhibition of AM oxidative burst.These observations provide additional information concerning the activity of interleukin-9 in the lung, related to inflammatory or fibrosing lung processes.

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“…IL9r was shown to inhibit both the production of reactive oxygen species and the release of TNF-α by LPS-stimulated human monocytes. 35 Via toll-like receptor 3, 36 stathmin is thought to mediate IL-10 induction, 37 which is increased in the plasma of apoE…”

Section: Grandoch Et Al Lymphotoxin β Receptor Promotes Atherosclerosmentioning

confidence: 99%

Deficiency in Lymphotoxin β Receptor Protects From Atherosclerosis in apoE-Deficient Mice

Grandoch

Feldmann

Göthert

et al. 2015

Circulation Research

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Rationale: Lymphotoxin β receptor (LTbR) regulates immune cell trafficking and communication in inflammatory diseases. However, the role of LTbR in atherosclerosis is still unclear. Objective: The aim of this study was to elucidate the role of LTbR in atherosclerosis. Methods and Results: After 15 weeks of feeding a Western-type diet, mice double-deficient in apolipoprotein E and LTbR (apoE −/− /LTbR −/− ) exhibited lower aortic plaque burden than did apoE −/− littermates. Macrophage content at the aortic root and in the aorta was reduced, as determined by immunohistochemistry and flow cytometry. In line with a decrease in plaque inflammation, chemokine (C–C motif) ligand 5 ( Ccl5 ) and other chemokines were transcriptionally downregulated in aortic tissue from apoE −/− /LTbR −/− mice. Moreover, bone marrow chimeras demonstrated that LTbR deficiency in hematopoietic cells mediated the atheroprotection. Furthermore, during atheroprogression, apoE −/− mice exhibited increased concentrations of cytokines, for example, Ccl5, whereas apoE −/− /LTbR −/− mice did not. Despite this decreased plaque macrophage content, flow cytometric analysis showed that the numbers of circulating lymphocyte antigen 6C (Ly6C) low monocytes were markedly elevated in apoE −/− /LTbR −/− mice. The influx of these cells into atherosclerotic lesions was significantly reduced, whereas apoptosis and macrophage proliferation in atherosclerotic lesions were unaffected. Gene array analysis pointed to chemokine (C–C motif) receptor 5 as the most regulated pathway in isolated CD115 + cells in apoE −/− /LTbR −/− mice. Furthermore, stimulating monocytes from apoE −/− mice with agonistic anti-LTbR antibody or the natural ligand lymphotoxin-α1β2, increased Ccl5 mRNA expression. Conclusions: These findings suggest that LTbR plays a role in macrophage-driven inflammation in atherosclerotic lesions, probably by augmenting the Ccl5-mediated recruitment of monocytes.

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IL-9 Inhibits Oxidative Burst and TNF-α Release in Lipopolysaccharide-Stimulated Human Monocytes Through TGF-β

Cited by 57 publications

References 43 publications

Activation-Induced Depletion of Protein Kinase Cα Provokes Desensitization of Monocytes/Macrophages in Sepsis

Activation-Induced Depletion of Protein Kinase Cα Provokes Desensitization of Monocytes/Macrophages in Sepsis

Oxidative burst in lipopolysaccharide-activated human alveolar macrophages is inhibited by interleukin-9

Deficiency in Lymphotoxin β Receptor Protects From Atherosclerosis in apoE-Deficient Mice

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