Perilla Leaf Extract Attenuates Asthma Airway Inflammation by Blocking the Syk Pathway
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Perilla frutescens (L.) Britton is a classic herbal plant used widely against asthma in China. But its mechanism of beneficial effect remains undermined. In the study, the antiallergic asthma effects of Perilla leaf extract (PLE) were investigated, and the underlying mechanism was also explored. Results showed that PLE treatment significantly attenuated airway inflammation in OVA-induced asthma mice, by ameliorating lung pathological changes, inhibiting recruitment of inflammatory cells in lung tissues and bronchoalveolar lavage fluid (BALF), decreasing the production of inflammatory cytokines in the BALF, and reducing the level of immunoglobulin in serum. PLE treatment suppressed inflammatory response in antigen-induced rat basophilic leukemia 2H3 (RBL-2H3) cells as well as in OVA-induced human peripheral blood mononuclear cells (PBMCs). Furthermore, PLE markedly inhibited the expression and phosphorylation of Syk, NF-κB, PKC, and cPLA2 both in vivo and in vitro. By cotreating with inhibitors (BAY61-3606, Rottlerin, BAY11-7082, and arachidonyl trifluoromethyl ketone) in vitro, results revealed that PLE's antiallergic inflammatory effects were associated with the inhibition of Syk and its downstream signals NF-κB, PKC, and cPLA2. Collectively, the present results suggested that PLE could attenuate allergic inflammation, and its mechanism might be partly mediated through inhibiting the Syk pathway.Keywords:
Perilla frutescens
Allergic Inflammation
Rottlerin
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The aim of this study was to determine the prognostic significance of the expression of Lyn, Fyn and Syk in Hodgkin lymphoma and its correlation with Epstein–Barr virus (EBV) infection. With this in mind, 96 patients with classical Hodgkin lymphoma were immunohistochemically evaluated for Lyn, Fyn and Syk expression in Hodgkin and Reed–Sternberg cells, and the results were correlated with the presence of EBV and patient outcomes. These three kinases were heterogeneously expressed in classical Hodgkin lymphoma cases. As there are no cut-offs established for these antibodies, they were introduced as continuous variables in the model. Statistical analysis showed that the expression of Syk and Fyn was significantly associated with shorter failure-free survival. Syk and Fyn may be useful to predict at diagnosis the treatment response of patients with classical Hodgkin lymphoma. There was a significant association between EBV infection and Lyn expression (p < 0.05). Overexpression of Syk and the availability of Syk inhibitors suggest that this molecule might be a therapeutic strategy worthy of development for cases expressing this molecule.
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Abstract Recent data indicate that phagocytosis mediated by FcγRs is controlled by the Src and Syk families of protein tyrosine kinases. In this study, we demonstrate a sequential involvement of Lyn and Syk in the phagocytosis of IgG-coated particles. The particles isolated at the stage of their binding to FcγRs (4°C) were accompanied by high amounts of Lyn, in addition to the signaling γ-chain of FcγRs. Simultaneously, the particle binding induced rapid tyrosine phosphorylation of numerous proteins. During synchronized internalization of the particles induced by shifting the cell to 37°C, Syk kinase and Src homology 2-containing tyrosine phosphatase-1 (SHP-1) were associated with the formed phagosomes. At this step, most of the proteins were dephosphorylated, although some underwent further tyrosine phosphorylation. Quantitative immunoelectron microscopy studies confirmed that Lyn accumulated under the plasma membrane beneath the bound particles. High amounts of the γ-chain and tyrosine-phosphorylated proteins were also observed under the bound particles. When the particles were internalized, the γ-chain was still detected in the region of the phagosomes, while amounts of Lyn were markedly reduced. In contrast, the vicinity of the phagosomes was heavily decorated with anti-Syk and anti-SHP-1 Abs. The local level of protein tyrosine phosphorylation was reduced. The data indicate that the accumulation of Lyn during the binding of IgG-coated particles to FcγRs correlated with strong tyrosine phosphorylation of numerous proteins, suggesting an initiating role for Lyn in protein phosphorylation at the onset of the phagocytosis. Syk kinase and SHP-1 phosphatase are mainly engaged at the stage of particle internalization.
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Abstract The Syk protein tyrosine kinase is an essential component of the B cell Ag receptor signaling pathway. Syk is phosphorylated on tyrosine following B cell activation. However, the sites that are modified and the kinases responsible for these modifications have yet to be determined. To approach this problem, we used a mapping strategy based on the electrophoretic separation of peptides on alkaline polyacrylamide gels to identify the tryptic phosphopeptides derived from metabolically labeled Syk. In this work, we report that Syk from activated B cells is phosphorylated principally on six tyrosines: one located between the tandem SH2 domains (Tyr130); three in the linker region (Tyr317, Tyr342, and Tyr346); and two in the catalytic domain (Tyr519 and Tyr520). The linker region sites are the primary targets of the Src family protein tyrosine kinase, Lyn, and include a site that negatively (Tyr317) regulates receptor signaling. Efficient phosphorylation of the catalytic domain and inter-SH2 domain tyrosines is catalyzed primarily by Syk itself, but only occurs to an appreciable extent in cells that express Lyn. We propose that these sites are phosphorylated following the binding of Syk to immunoreceptor tyrosine-based activation motif.
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Radiation-induced biochemical events that mediate the intracellular signal transduction leading to cell apoptosis are largely unknown. Limited evidence suggests the possible involvement of one or more protein-tyrosine kinases (PTKs) in radiation-induced cellular responses, including apoptosis. However, so far, a PTK(s) responsible for the radiation-induced tyrosine phosphorylation of cellular substrates has not been identified and the role of the PTK(s) in the radiation-induced apoptosis remains unclear. To examine the roles of Syk and Lyn in radiation-induced signal transduction and radiation-induced apoptosis, we analyzed Syk-deficient or Lyn-deficient DT40 B cells along with wild-type cells following radiation. When DT40 B cells were exposed to radiation, the activity of Syk kinase dramatically increased and reached a maximum with 0.25 Grays (Gy) (15 s), and then decreased, whereas Lyn kinase activity increased and reached a maximum with a dose of 1.00 Gy (1 min). However, an apparent difference was not observed in radiation-induced apoptosis among wild-type, Syk-deficient, and Lyn-deficient DT40 B cells. These results indicate that Syk and Lyn kinases are involved in radiation-induced signal transduction, with different kinetics. In addition, our results revealed that functional inactivation of Syk or Lyn alone is not sufficient to prevent radiation-induced apoptosis. Thus, it is suggested that the activation of Syk or Lyn kinase alone may be sufficient to mediate the radiation-induced apoptosis in DT40 B cells, or both kinases may not be required for this biological process
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Src family kinase
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High affinity IgE receptors (alpha beta gamma 2) mediate the activation of the non-receptor tyrosine kinases Lyn and Syk. Here we show that the antioxidant drug N-acetyl-L-cysteine (NAC) inhibits antigen-mediated Syk activation whereas Lyn activation and phosphorylation of beta and gamma is maintained. Furthermore, NAC inhibits antigen-mediated calcium mobilization and exocytosis in a dose-dependent manner, but does not inhibit ionomycin-induced exocytosis. These data support a model in which the activation of Lyn is responsible for receptor phosphorylation and precedes the activation of Syk. The inhibition of Syk activation by NAC may be relevant to B and T cell antigen receptors, which are also linked to Syk/ZAP70 tyrosine kinases.
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Activation of rat mast cells through the receptor with high affinity for IgE (Fc epsilonRI) requires a complex set of interactions involving transmembrane subunits of the Fc epsilonRI and two classes of nonreceptor protein tyrosine kinase (PTK). the Src family PTK p53/p56(lyn) (Lyn) and the Syk/ZAP-family PTK p72(syk) (Syk). Early activation events involve increased activity of Lyn and Syk kinases and their translocation into membrane domains containing aggregated Fc epsilonRI, but the molecular mechanisms responsible for these changes have remained largely unclear. To determine the role of Fc epsilonRI subunits in this process, we have analyzed Syk- and Lyn-associated proteins in activated rat basophilic leukemia (RBL) cells and their variants deficient in the expression of Fc epsilonRI beta or gamma subunits. Sepharose 4B gel chromatography of postnuclear supernatants from Nonidet-P40-solubilized antigen (Ag)- or pervanadate-activated RBL cells revealed extensive changes in the size of complexes formed by Lyn and Syk kinases and other cellular components. A fusion protein containing Src homology 2 (SH2) and SH3 domains of Lyn bound Syk from lysates of nonactivated RBL cells; an increased binding was observed when lysates from Ag- or pervanadate-activated cells were used. A similar amount of Syk was bound when lysates from pervanadate-activated variant cells deficient in the expression of Fc epsilonRI beta or gamma subunits were used, suggesting that Fc epsilonRI does not function as the only intermediate in the formation of the Syk-Lyn complexes. Further experiments have indicated that Syk-Lyn interactions occur in Ag-activated RBL cells under in vivo conditions and that these interactions could involve direct binding of the Lyn SH2 domain with phosphorylated tyrosine of Syk. The physical association of Lyn and Syk during mast-like cell activation supports the recently proposed functional cooperation of these two tyrosine kinases in Fc epsilonRI signaling.
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A chicken B cell line DT40 and its syk ‐negative or lyn ‐negative mutants were used to investigate the roles of protein‐tyrosine kinases in oxidant stress signaling. The data presented here for wild‐type cells demonstrate that hydrogen peroxide stimulates p53/56 lyn ‐dependent tyrosine phosphorylation and activation of p72 syk , and induces a rapid and prolonged elevation of intracellular calcium, which consists of calcium release from intracellular stores and influx from the extracellular space. Hydrogen‐peroxide‐triggered calcium mobilization was impaired in both syk ‐negative and lyn ‐negative cells, which was mainly due to the loss of calcium release from intracellular stores. Further studies indicated that inositol trisphosphate production was also abolished in both syk ‐negative and lyn ‐negative cells, which is consistent with the loss of calcium release. Taken together, these observations suggest that the defect of p72 syk or p53/56 lyn was responsible for the abnormality of calcium mobilization in both lyn ‐negative and syk ‐negative cells, and that both p72 syk and p53/56 lyn might regulate calcium mobilization through the phospha‐tidylinositol pathway in B cell oxidant stress signaling.
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Calcium in biology
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