IL‐5 priming of the PMA‐induced oxidative metabolism of human eosinophils from allergic and normal subjects during a pollen season

Woschnagg, Charlotte; García, Rafael Martínez; Rak, S.

doi:10.1046/j.1365-2222.2001.00995.x

Cited by 13 publications

(12 citation statements)

References 39 publications

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“…The function of human eosinophils is largely regulated by IL-5 family cytokines, including IL-5, IL-3 and GM-CSF (7–10). Recently, several lines of evidence demonstrate that IL-5 family members can enhance blood eosinophil responsiveness to a second stimulus, such as the chemotactic factors CCL5 and formyl-Met-Leu-Phe (fMLP), resulting in a synergistic response known as “priming” (10–15). The capacity of IL-5 family cytokines to prime blood eosinophils for altered chemoattractant responsiveness has been associated with changes in intracellular signaling events, e.g.…”

Section: Introductionmentioning

confidence: 99%

“…The capacity of IL-5 family cytokines to prime blood eosinophils for altered chemoattractant responsiveness has been associated with changes in intracellular signaling events, e.g. an increase in chemoattractant-induced phosphorylation of the mitogen-activated protein kinases ERK1 and 2 (11), and biological responses, such as chemotaxis, degranulation and the release of proinflammatory mediators (7, 9, 10, 12, 14, 15). Furthermore, the priming of blood eosinophils with IL-5 family members allows for these cells to exhibit a similar phenotype and hyper-responsiveness as that observed with airway eosinophils (9, 16–19).…”

Section: Introductionmentioning

confidence: 99%

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Chemoattractant-Induced Signaling via the Ras–ERK and PI3K–Akt Networks, along with Leukotriene C4 Release, Is Dependent on the Tyrosine Kinase Lyn in IL-5– and IL-3–Primed Human Blood Eosinophils

Zhu

Bertics

2011

The Journal of Immunology

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Human blood eosinophils exhibit a hyper-active phenotype in response to chemotactic factors following cell “priming” with IL-5 family cytokines. Earlier work has identified ERK1/2 as molecular markers for IL-5 priming, and herein we show that IL-3, a member of IL-5 family, also augments fMLP-stimulated ERK1/2 phosphorylation in primary eosinophils. Besides ERK1/2, we also observed an enhancement of chemotactic factor-induced Akt phosphorylation following IL-5 priming of human blood eosinophils. Administration of a peptide antagonist that targets the Src family member Lyn prior to cytokine (IL-5/IL-3) priming of blood eosinophils inhibited the synergistic increase of fMLP-induced activation of Ras, ERK1/2 and Akt, as well as the release of the proinflammatory factor leukotriene-C4. In the current study, we also examined a human eosinophil-like cell line HL-60 clone-15, and observed that these cells exhibited significant surface expression of IL-3 and GM-CSF receptors, as well as ERK1/2 phosphorylation in response to the addition of IL-5 family cytokines or the chemotactic factors fMLP, CCL5 and CCL11. Consistent with the surface profile of IL-5 family receptors, HL-60 clone-15 recapitulated the enhanced fMLP-induced ERK1/2 phosphorylation observed in primary blood eosinophils following priming with IL-3/GM-CSF, and siRNA-mediated knockdown of Lyn expression completely abolished the synergistic effects of IL-3 priming on fMLP-induced ERK1/2 phosphorylation. Altogether, our data reveal a central role for Lyn in the mechanisms of IL-5 family priming, and suggest that Lyn contributes to the up-regulation of the Ras-ERK1/2 and PI3K-Akt cascades as well as the increased leukotriene-C4 release observed in response to fMLP in “primed” eosinophils.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemoattractant-Induced Signaling via the Ras–ERK and PI3K–Akt Networks, along with Leukotriene C4 Release, Is Dependent on the Tyrosine Kinase Lyn in IL-5– and IL-3–Primed Human Blood Eosinophils

Zhu

Bertics

2011

The Journal of Immunology

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“…For instance, eosinophils purified from symptomatic asthmatics generate higher ROS on activation of plateletactivating factor or phorbol myristate acetate than those of asymptomatic asthmatics [16]. This study demonstrated that ketotifen inhibited the production of ROS from eotaxin-primed human eosinophils at concentrations of 10 -10 -10 -6 mol/l.…”

Section: Discussionmentioning

confidence: 67%

Effect of Ketotifen on the Production of Reactive Oxygen Species from Human Eosinophils Primed by Eotaxin

Yamada

Sannohe²,

Saito³

et al. 2003

Pharmacology

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Ketotifen is an antiallergic drug and may have direct inhibitory effects on eosinophils. To investigate the anti-eosinophilic effect of ketotifen, we examined the effect of ketotifen on the production of reactive oxygen species (ROS) from eotaxin-primed human eosinophils. Ketotifen at 10^–10–10^–6 mol/l significantly reduced the production of ROS evoked by A23187 from eosinophils primed by eotaxin. In contrast, ketotifen at 10^–5 mol/l significantly augmented the production in the absence of eotaxin. We demonstrated that appropriate concentrations of ketotifen may have direct inhibitory effects on eosinophil oxidative metabolism primed by eotaxin. Ketotifen may contribute to the treatment of allergic disease through its anti-eosinophilic effects.

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“…Gö 6983 was found to strongly inhibit superoxide anion release from eosinophils isolated from human patients allergic to birch pollen (77). This finding suggests that Gö 6983 may be effective in inhibiting symptoms associated with rhinitis or asthma.…”

Section: Clinical Studies With Gö 6983 and Other Pkc Inhibitorsmentioning

confidence: 82%

“…Gö 6983 represents a potentially useful therapeutic tool in settings of exaggerated immune responses (i.e., allergic) to attenuate leukocyte activity. Gö 6983 was found to strongly inhibit superoxide anion release from eosinophils isolated from human patients allergic to birch pollen (77). This finding suggests that Gö 6983 may be effective in inhibiting symptoms associated with rhinitis or asthma.…”

Section: Clinical Studies With Gö 6983 and Other Pkc Inhibitorsmentioning

confidence: 82%

Gö 6983: A Fast Acting Protein Kinase C Inhibitor that Attenuates Myocardial Ischemia/Reperfusion Injury

Young

Balin

Weis

2006

Cardiovascular Drug Reviews

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Reperfusion injury is characterized by a decrease in endothelial release of nitric oxide within 5 min after reperfusion, increased leukocyte-endothelium interaction, and transmigration of leukocytes into the myocardium, producing cardiac contractile dysfunction. Gö 6983 is a fast acting, lipid soluble, broad spectrum protein kinase C inhibitor. When administered at the beginning of reperfusion, it can restore cardiac function within 5 min and attenuate the deleterious effects associated with acute ischemia/reperfusion. Gö 6983 may offer greater cardioprotection than other broad-spectrum PKC inhibitors in postischemic reperfusion injury because it inhibits PKC(zeta) as well as four other isoforms. The cardioprotection is associated with decreased leukocyte superoxide release and increased endothelial derived nitric oxide from vascular tissue. In vitro studies of human tissue showed that Gö 6983 significantly inhibited antigen-induced superoxide release from leukocytes of patients previously sensitized to tree pollen. In human vascular tissue, Gö 6983 inhibited intracellular Ca(2+) accumulation, suggesting a mechanism for its vasodilator properties. These studies suggest that Gö 6983 would be an effective compound to use in a clinical ischemia/reperfusion setting of organ transplantation and/or cerebral ischemia where inhibiting superoxide release and vasoconstriction in postischemic tissues would allow for better restoration of organ function during reperfusion. However, given the broad-spectrum action of Gö 6983, careful titration of the dose regimen would be recommended to ensure a successful outcome in the setting of organ transplantation and/or cerebral ischemia.

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IL‐5 priming of the PMA‐induced oxidative metabolism of human eosinophils from allergic and normal subjects during a pollen season

Cited by 13 publications

References 39 publications

Chemoattractant-Induced Signaling via the Ras–ERK and PI3K–Akt Networks, along with Leukotriene C4 Release, Is Dependent on the Tyrosine Kinase Lyn in IL-5– and IL-3–Primed Human Blood Eosinophils

Chemoattractant-Induced Signaling via the Ras–ERK and PI3K–Akt Networks, along with Leukotriene C4 Release, Is Dependent on the Tyrosine Kinase Lyn in IL-5– and IL-3–Primed Human Blood Eosinophils

Effect of Ketotifen on the Production of Reactive Oxygen Species from Human Eosinophils Primed by Eotaxin

Gö 6983: A Fast Acting Protein Kinase C Inhibitor that Attenuates Myocardial Ischemia/Reperfusion Injury

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