Platelet-activating factor activates mitogen-activated protein kinases through the activation of phosphatidylinositol 3-kinase and tyrosine kinase in human eosinophils

Miike, Satoshi; Kurasawa, Kazuhiro; Saitō, Yasushi; Iwamoto, Itsuo

doi:10.1002/jlb.67.1.117

Cited by 39 publications

(48 citation statements)

References 79 publications

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“…In contrast, studies characterizing the G protein(s) coupled to the PAF receptor in primary granulocytes have been controversial. For example, the PAF-induced [Ca 2ϩ ] i response of guinea pig eosinophils was resistant to PTX (24), while the [Ca 2ϩ ] i response of human eosinophils was sensitive (21,26,27). In human neutrophils the increased [Ca 2ϩ ] i stimulated with PAF was not blocked by PTX (28).…”

Section: Discussionmentioning

confidence: 99%

“…However, the nature of G proteins involved in the PAF response is more complex. For example, the [Ca 2ϩ ] i response and MAPK activation of human eosinophils are inhibited by PTX (21,26,27). In contrast, in human neutrophils the increases in [Ca 2ϩ ] i and activation of Ral are not inhibited by PTX (28).…”

Section: P Latelet-activating Factor (Paf)mentioning

confidence: 98%

“…To circumvent the problem, we studied a specific, upstream candidate molecule in eosinophil tyrosine kinase pathways. It has been shown that PAF activates eosinophil PI3K (21,43). Therefore, we tested an inhibitor of PI3K, wortmannin, on the PAF-induced chemiluminescence response.…”

Section: The Second- But Not the First- Phase Response Is Dependentmentioning

confidence: 99%

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Platelet-Activating Factor Activates Two Distinct Effector Pathways in Human Eosinophils

Katô

Kimura

Motegi

et al. 2002

The Journal of Immunology

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In granulocytes, platelet-activating factor (PAF) shares many of its biological effects with other chemotactic factors, such as FMLP, complement fragments, and lipid mediators. Two unique effects are that PAF is relatively resistant to pertussis toxin (PTX) and that PAF activates the inflammatory functions of eosinophils more strongly than it activates those of neutrophils. To investigate the molecular mechanisms of the responses of eosinophils to PAF, we analyzed superoxide anion production by a chemiluminescence method that provides real-time kinetic data for the cellular responses. We found that PAF induced bimodal superoxide anion production in human eosinophils, consisting of an intense, but transient, first phase and a larger and sustained second phase. In contrast, PAF induced essentially a transient unimodal response in human neutrophils. The two phases of eosinophil response were mediated by distinct cellular mechanisms: the second phase was highly dependent on cellular adhesion and β2 integrins, but the first phase was independent of both adhesion and β2 integrins. The upstream signaling mechanisms were also different: the second phase was mediated by PTX-resistant G-protein(s) and through activation of phosphatidylinositol 3-kinase, while the first phase was mediated by PTX-sensitive G-protein(s). Furthermore, the second-phase response was ∼100-fold more resistant to inhibition by a competitive PAF receptor antagonist than the first phase. Thus, eosinophils and neutrophils react differently to PAF, and PAF activates two separate and distinct effector pathways in human eosinophils. These two activation pathways may explain the eosinophils’ strong and diverse biological responses to PAF.

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Section: Discussionmentioning

confidence: 99%

Section: P Latelet-activating Factor (Paf)mentioning

confidence: 98%

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Platelet-Activating Factor Activates Two Distinct Effector Pathways in Human Eosinophils

Katô

Kimura

Motegi

et al. 2002

The Journal of Immunology

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“…Kinases have been found to localize at the cell nucleus (20), are involved in immediate-early gene induction (41), and PAF has been reported to induce MAPK activation (42). C-PAF evoked a time-dependent ERK1/2 phosphorylation in isolated nuclei; total ERK remained unchanged (Fig.…”

Section: Gene Transcription By Paf In Isolated Nucleimentioning

confidence: 94%

Proinflammatory Gene Induction by Platelet-Activating Factor Mediated Via Its Cognate Nuclear Receptor

Marrache

Gobeil

Bernier

et al. 2002

The Journal of Immunology

114

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It has been postulated that intracellular binding sites for platelet-activating factor (PAF) contribute to proinflammatory responses to PAF. Isolated nuclei from porcine cerebral microvascular endothelial cells (PCECs) produced PAF-molecular species in response to H2O2. Using FACS analysis, we demonstrated the expression of PAF receptors on cell and nuclear surfaces of PCECs. Confocal microscopy studies performed on PCECs, Chinese hamster ovary cells stably overexpressing PAF receptors, and isolated nuclei from PCECs also showed a robust nuclear distribution of PAF receptors. Presence of PAF receptors at the cell nucleus was further revealed in brain endothelial cells by radioligand binding experiments, immunoblotting, and in situ in brain by immunoelectron microscopy. Stimulation of nuclei with methylcarbamate-PAF evoked a decrease in cAMP production and a pertussis toxin-sensitive rise in nuclear calcium, unlike observations in plasma membrane, which exhibited a pertussis toxin-insensitive elevation in inositol phosphates. Moreover, on isolated nuclei methylcarbamate-PAF evoked the expression of proinflammatory genes inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) and was associated with augmented extracellular signal-regulated kinase 1/2 phosphorylation and NF-κB binding to the DNA consensus sequence. COX-2 expression was prevented by mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 and NF-κB inhibitors. This study describes for the first time the nucleus as a putative organelle capable of generating PAF and expresses its receptor, which upon stimulation induces the expression of the proinflammatory gene COX-2.

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“…37 PAF is a potent activator of mitogen-activated protein kinase, 38 signal transducer and activator of transcription-3 39 and phosphoinositol-3 kinase. 40 In vivo, PAF has been shown to be produced in a model of endotoxic shock 20 and to mediate LPS-induced intestinal injury. 20 PAF was also found to mediate LPS-induced NF-jB activation.…”

Section: Cxcl2 C C Lps Ctrol Abmentioning

confidence: 99%

Lipopolysaccharide induces CXCL2/macrophage inflammatory protein‐2 gene expression in enterocytes via NF‐κB activation: independence from endogenous TNF‐α and platelet‐activating factor

Plaen¹,

Han²,

Liu³

et al. 2006

Immunology

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SummaryCXCL2 (macrophage inflammatory protein-2 (MIP-2)), a critical chemokine for neutrophils, has been shown to be produced in the rat intestine in response to platelet-activating factor (PAF) and to mediate intestinal inflammation and injury. The intestinal epithelium, constantly exposed to bacterial products, is the first line of defence against micro-organisms. It has been reported that enterocytes produce proinflammatory mediators, including tumour necrosis factor (TNF) and PAF, and we showed that lipopolysaccharide (LPS) and TNF activate nuclear factor (NF)-jB in enterocytes. However, it remains elusive whether enterocytes release CXCL2 in response to LPS and TNF via a NF-jB-dependent pathway and whether this involves the endogenous production of TNF and PAF. In this study, we found that TNF and LPS markedly induced CXCL2 gene expression in IEC-6 cells, TNF within 30 min, peaking at 45 min, while LPS more slowly, peaking after 2 hr. TNF-and LPS-induced CXCL2 gene expression and protein release were completely blocked by pyrrolidine dithiocarbamate (PDTC) and helenalin, two potent NF-jB inhibitors. NEMO-binding domain peptide, a specific inhibitor of inhibitor protein jB kinase (IKK) activation, a major upstream kinase mediating NF-jB activation, significantly blocked CXCL2 gene expression and protein release induced by LPS. WEB2170 (PAF antagonist) and anti-TNF antibodies had no effect on LPS-induced CXCL2 expression. In conclusion, CXCL2 gene is expressed in enterocytes in response to both TNF and LPS. LPS-induced CXCL2 expression is dependent on NF-jB activation via the IKK pathway. The effect of LPS is independent of endogenous TNF and PAF.

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Platelet-activating factor activates mitogen-activated protein kinases through the activation of phosphatidylinositol 3-kinase and tyrosine kinase in human eosinophils

Cited by 39 publications

References 79 publications

Platelet-Activating Factor Activates Two Distinct Effector Pathways in Human Eosinophils

Platelet-Activating Factor Activates Two Distinct Effector Pathways in Human Eosinophils

Proinflammatory Gene Induction by Platelet-Activating Factor Mediated Via Its Cognate Nuclear Receptor

Lipopolysaccharide induces CXCL2/macrophage inflammatory protein‐2 gene expression in enterocytes via NF‐κB activation: independence from endogenous TNF‐α and platelet‐activating factor

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