Mechanism of interleukin-13 production by granulocyte-macrophage colony-stimulating factor-dependent macrophages via protease-activated receptor-2

Yamaguchi, Rui; Yamamoto, Tomohisa; Sakamoto, Arisa; Ishimaru, Yasuji; Narahara, Sayoko; Sugiuchi, Hiroyuki; Hirose, Eiji

doi:10.1016/j.bcmd.2015.03.006

Cited by 23 publications

(12 citation statements)

References 34 publications

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“…Although GM-CSF is frequently used to induce M1 polarization in human macrophages (5,32), in our hands, GM-CSF was also a potent inducer of M2 ATM polarization. Notably, GM-CSF has been shown to stimulate IL-13 expression in macrophages in vitro and in vivo (33)(34)(35), as well as the expression of CD206 (36), a surface marker of M2 macrophages.…”

Section: Discussionmentioning

confidence: 99%

IL-6 Regulates M2 Polarization and Local Proliferation of Adipose Tissue Macrophages in Obesity

Braune

Weyer

Hobusch

et al. 2017

The Journal of Immunology

203

158

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Obesity is associated with chronic low-grade inflammation of adipose tissue (AT) and an increase of AT macrophages (ATMs) that is linked to the onset of type 2 diabetes. We have recently shown that focal sites of inflammation around dying adipocytes, so-called crown-like structures, exhibit a unique microenvironment for macrophage proliferation. Interestingly, locally proliferating macrophages were not classically activated (M1), but they exhibited a rather alternatively activated (M2) immune phenotype. In this study, we established organotypic cell cultures of AT explants to study the impact of cytokine treatment on local ATM proliferation, without the bias of early monocyte recruitment. We show that exposure of AT to Th2 cytokines, such as IL-4, IL-13, and GM-CSF, stimulates ATM proliferation, whereas Th1 cytokines, such as TNF-α, inhibit local ATM proliferation. Furthermore, AT from obese mice exhibits an increased sensitivity to IL-4 stimulation, indicated by an increased phosphorylation of STAT6. In line with this, gene expression of the IL-4 receptor () and its ligand IL-13 are elevated in AT of obese C57BL/6 mice. Most importantly, expression and susceptibility to IL-4 or IL-13 treatment depend on IL-6 signaling, which seems to be the underlying mechanism of local ATM proliferation in obesity. We conclude that IL-6 acts as a Th2 cytokine in obesity by stimulating M2 polarization and local ATM proliferation, presumably due to upregulation of the IL-4 receptor α.

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Section: Discussionmentioning

confidence: 99%

IL-6 Regulates M2 Polarization and Local Proliferation of Adipose Tissue Macrophages in Obesity

Braune

Weyer

Hobusch

et al. 2017

The Journal of Immunology

203

158

View full text Add to dashboard Cite

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“…On days 3 and 6 of culture, the cells were washed and fresh medium containing GM-CSF was added. After further incubation until day 9, the cells were utilized as GM-CSF-dependent macrophages [20] .…”

Section: Methodsmentioning

confidence: 99%

Roles of myeloperoxidase and GAPDH in interferon-gamma production of GM-CSF-dependent macrophages

Yamaguchi

Yamamoto

Sakamoto

et al. 2016

Heliyon

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Interferon (IFN)-gamma is highly expressed in atherosclerotic lesions and may have an important role in atherogenesis. Myeloperoxidase (MPO), the most abundant protein in neutrophils, is a marker of plaque vulnerability and a possible bridge between inflammation and cardiovascular disease. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has also been implicated in the pathogenesis of atherosclerosis. The present study investigated the role of neutrophil activation in atherosclerosis. Adherent macrophages were obtained from primary cultures of human mononuclear cells. Expression of IFN-gamma protein by GM-CSF-dependent-macrophages was investigated by enzyme-linked immunosorbent assay after stimulation with MPO. GM-CSF enhanced macrophage expression of the mannose receptor (CD206), which is involved in MPO uptake. MPO increased IFN-gamma production by GM-CSF-dependent macrophages in a concentration-dependent manner. Pretreatment of macrophages with small interfering RNA (siRNA) for CD206 or extracellular signal-regulated kinase (ERK)-2 attenuated IFN-gamma production, while siRNA for ERK-1 did not. GAPDH is known to bind to adenylate/uridylate (AU)-rich elements of RNA and may influence IFN-gamma protein expression by binding to the AU-rich element of IFN-gamma mRNA. Interestingly, pretreatment with siRNA for GAPDH significantly reduced IFN-gamma production by macrophages, while it did not affect TF protein expression. In conclusion, MPO upregulates IFN-gamma production by GM-CSF-dependent-macrophages via the CD206/ERK-2 signaling pathway, while silencing GAPDH reduces IFN-gamma production.

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“…Among the neutrophil granule proteins, neutrophil elastase activates protease‐activated receptor 2 (PAR‐2) and contributes to the regulation of inflammatory and immune responses (Ramachandran et al, ). Recently, we reported that PAR‐2 expression is upregulated in GM‐CSF‐dependent macrophages (Yamaguchi et al, ). Previous findings have suggested that PAR‐2 is involved in regulation of apoptosis (Ahmad et al, ), and it has been reported that p53 promotes apoptosis through both transcription‐dependent and ‐independent mechanisms (Fridman and Lowe, ).…”

Section: Introductionmentioning

confidence: 99%

A protease‐activated receptor 2 agonist (AC‐264613) suppresses interferon regulatory factor 5 and decreases interleukin‐12p40 production by lipopolysaccharide‐stimulated macrophages: Role of p53

Yamaguchi

Yamamoto

Sakamoto

et al. 2016

Cell Biology International

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The transcription factor interferon regulatory factor 5 (IRF5) has a key role in the production of interleukin (IL)-12 by macrophages. IRF5 is also a central mediator of toll-like receptor signaling and is a direct target of p53. Activation of protease-activated receptor 2 (PAR-2) upregulates p53 and suppresses apoptosis. This study investigated the influence of human neutrophil elastase (HNE) and PAR-2 agonists on expression of IRF5 and IL-12p40 by macrophages stimulated with lipopolysaccharide. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent macrophages showed upregulation of IRF5 expression, while HNE reduced expression of p53 and IRF5 in a concentration-dependent manner. HNE also caused a concentration-dependent decrease of IRF5 in macrophages transfected with small interfering RNA to silence p53, while silencing of β-arrestin 2 blunted the reduction of p53 or IRF5 by HNE. Incubation of macrophages with a PAR-2 agonist, AC-264613, caused a decrease of IRF5 expression and also significantly reduced p53 protein expression. HNE upregulated the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) and caused transactivation of TLR4, while AC-264613 did not promote TLR4 transactivation. In conclusion, the PAR-2 agonist AC-264613 attenuated IRF5-associated IL-12p40 production by macrophages.

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Mechanism of interleukin-13 production by granulocyte-macrophage colony-stimulating factor-dependent macrophages via protease-activated receptor-2

Cited by 23 publications

References 34 publications

IL-6 Regulates M2 Polarization and Local Proliferation of Adipose Tissue Macrophages in Obesity

IL-6 Regulates M2 Polarization and Local Proliferation of Adipose Tissue Macrophages in Obesity

Roles of myeloperoxidase and GAPDH in interferon-gamma production of GM-CSF-dependent macrophages

A protease‐activated receptor 2 agonist (AC‐264613) suppresses interferon regulatory factor 5 and decreases interleukin‐12p40 production by lipopolysaccharide‐stimulated macrophages: Role of p53

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