Interleukin-15 Inhibits Spontaneous Apoptosis in Human Eosinophils via Autocrine Production of Granulocyte Macrophage–Colony Stimulating Factor and Nuclear Factor- κ B Activation

Hoontrakoon, Raweewan; Chu, Hong Wei; Gardai, Shyra J.; Wenzel, Sally E.; McDonald, Patrick P.; Fadok, Valerie A.; Henson, Peter M.; Bratton, Donna L.

doi:10.1165/ajrcmb.26.4.4517

Cited by 73 publications

(47 citation statements)

References 53 publications

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“…The role of ␥c-dependent cytokines on eosinophil survival has been studied to some extent before. In particular, IL-9 and IL-15 (21) have been implicated in enhanced eosinophil survival, whereas IL-2 and IL-4 showed no effects and might increase apoptosis, respectively. Moreover, recently IL-7 has been proposed to contribute to increased eosinophil survival in the airways (22).…”

Section: Discussionmentioning

confidence: 97%

Common γ-Chain-Dependent Signals Confer Selective Survival of Eosinophils in the Murine Small Intestine

Carlens

Wahl

Ballmaier

et al. 2009

The Journal of Immunology

101

145

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Eosinophils are potent effector cells that are recruited to sites of inflammation. However, in some tissues, in particular in the gastrointestinal tract, eosinophils constitute an abundant leukocyte population also under homeostatic conditions. The lack of suitable isolation protocols restricted the analysis of these cells to histological assessment of cell numbers while important aspects of their phenotype, turnover, and functions remain unresolved. In this study, we report a protocol that allows the quantitative isolation of intestinal eosinophils. We characterized small intestinal eosinophils by flow cytometry as SSChighCD11b+CD11c+CCR3+Siglec-F+ cells. Intestinal eosinophils resembled eosinophils isolated from thymus and uterus but differed from eosinophils isolated from lung or blood. Eosinophils in intestine, thymus, and uterus showed in vivo a markedly higher life time compared with eosinophils present in lung and blood measured by incorporation of BrdU. This indicates that under steady-state conditions homeostasis of eosinophils is controlled by regulation of cell survival. Intestinal eosinophils are severely reduced in the intestines of Rag-2/common γ-chain double-deficient mice but not Rag-2-deficient mice, correlating with differential expression of GM-CSF and CCL11 in both mouse strains. Moreover, under steady-state conditions, intestinal eosinophils constitutively express high levels of the common γ-chain transcripts compared with lung eosinophils as well as eosinophils present under inflammatory conditions. These observations reveal a hitherto unrecognized diversity in phenotypic and functional properties of eosinophils and suggest that tissue-specific common γ-chain-dependent signals might profoundly affect eosinophil function and homeostasis.

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Section: Discussionmentioning

confidence: 97%

Common γ-Chain-Dependent Signals Confer Selective Survival of Eosinophils in the Murine Small Intestine

Carlens

Wahl

Ballmaier

et al. 2009

The Journal of Immunology

101

145

View full text Add to dashboard Cite

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“…Eosinophils were isolated from mildly allergic donors and cultured according to Hoontrakoon et al (2). To summarize, cells were isolated by a negative immunomagnetic procedure and transferred to 5-ml polypropylene tubes in 1-ml aliquots (0.5 million/ml), and cultured in Iscove's medium (Life Technologies, Grand Island, NY) with 20% FCS (HyClone Laboratories, Logan UT).…”

Section: Eosinophil Isolation and Culturementioning

confidence: 99%

“…Prosurvival HGSFs, and particularly GM-CSF, have been implicated in inhibiting eosinophil apoptosis in vitro and in vivo (2,4,5,12,44). It has been shown that IL-5 (in the absence of GC) inhibits Bax activation/translocation, mitochondrial damage, cytochrome c release, caspase activation, and subsequent apoptosis (10,12).…”

Section: Gm-csf Addition Inhibits Gc-induced Mitochondrial Damage Andmentioning

confidence: 99%

Oxidant-Mediated Mitochondrial Injury in Eosinophil Apoptosis: Enhancement by Glucocorticoids and Inhibition by Granulocyte-Macrophage Colony-Stimulating Factor

Gardai

Hoontrakoon

Goddard

et al. 2003

The Journal of Immunology

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The mainstay of asthma therapy, glucocorticosteroids (GCs) have among their therapeutic effects the inhibition of inflammatory cytokine production and induction of eosinophil apoptosis. In the absence of prosurvival cytokines (e.g., GM-CSF), eosinophils appear to be short-lived, undergoing apoptosis over 96 h in vitro. In a dose-dependent manner, GC further enhances apoptosis, while prosurvival cytokines inhibit apoptosis and antagonize the effect of GC. The mechanisms of eosinophil apoptosis, its enhancement by GC, and antagonism of GC by GM-CSF are not well-understood. As demonstrated in this study, baseline apoptosis of eosinophils resulted from oxidant-mediated mitochondrial injury that was significantly enhanced by GC. Mitochondrial injury was detected by early and progressive loss of mitochondrial membrane potential and the antioxidant protein, Mn superoxide dismutase (SOD). Also observed was the activation/translocation of the proapoptotic protein, Bax, to mitochondria. Underscoring the role of oxidants was the inhibition of mitochondrial changes and apoptosis with culture in hypoxia, or pretreatment with a flavoprotein inhibitor or a SOD mimic. GCs demonstrated early (40 min) and late (16 h) activation of proapoptotic c-Jun NH2-terminal kinase (JNK) and decreased the antiapoptotic protein X-linked inhibitor of apoptosis, a recently demonstrated inhibitor of JNK activation. Similarly, inhibition of JNK prevented GC-enhanced mitochondrial injury and apoptosis. Importantly, GM-CSF prevented GC-induced loss of X-linked inhibitor of apoptosis protein, late activation of JNK, and mitochondrial injury even in the face of unchanged oxidant production, loss of MnSOD, and early JNK activation. These data demonstrate that oxidant-induced mitochondrial injury is pivotal in eosinophil apoptosis, and is enhanced by GC-induced prolonged JNK activation that is in turn inhibited by GM-CSF.

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“…It has been appreciated for some time that IL-3, granulocytemacrophage colony-stimulating factor and IL-5 enhance eosinophil survival and therefore eosinophil persistence in the tissues may be prolonged in their presence. Additionally, IL-13 (Luttmann et al 1996, Horie et al 1997, IL-9 (Gounni et al 2000) and IL-15 (Hoontrakoon et al 2002) have all been shown to enhance eosinophil survival. The significance of these findings is emphasised by ample evidence that these cytokines are present in asthmatic airway tissue and that eosinophils isolated from patients with atopic dermatitis and, to a lesser extent inhalant allergy, displayed enhanced survival compared with normal controls (Wedi et al 1997).…”

Section: Eosinophil Apoptosismentioning

confidence: 99%

Corticosteroids, eosinophils and bronchial epithelial cells: new insights into the resolution of inflammation in asthma

Walsh¹,

Sexton²,

Blaylock³

2003

Journal of Endocrinology

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Anti-inflammatory therapy in asthma is reliant on corticosteroids, particularly in their inhaled form. However, steroids are rather non-specific in their actions and they also raise concerns regarding compliance and side-effect issues. Furthermore, a small proportion of patients with asthma fail to respond to oral glucocorticoids even at high doses. This article will review the role that steroids and membrane receptor ligation play in the induction of eosinophil apoptosis together with the mechanisms by which corticosteroids enhance the disposal of apoptotic eosinophils by both professional and non-professional phagocytes. Eosinophils are thought to be the major pro-inflammatory effector cell in asthma and their persistence in the airways is probably enhanced by the presence of several asthma-relevant cytokines that prolong eosinophil survival by inhibition of apoptosis (interleukin (IL)-3, IL-5, granulocyte-macrophage colony-stimulating factor,

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Interleukin-15 Inhibits Spontaneous Apoptosis in Human Eosinophils via Autocrine Production of Granulocyte Macrophage–Colony Stimulating Factor and Nuclear Factor- κ B Activation

Cited by 73 publications

References 53 publications

Common γ-Chain-Dependent Signals Confer Selective Survival of Eosinophils in the Murine Small Intestine

Common γ-Chain-Dependent Signals Confer Selective Survival of Eosinophils in the Murine Small Intestine

Oxidant-Mediated Mitochondrial Injury in Eosinophil Apoptosis: Enhancement by Glucocorticoids and Inhibition by Granulocyte-Macrophage Colony-Stimulating Factor

Corticosteroids, eosinophils and bronchial epithelial cells: new insights into the resolution of inflammation in asthma

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