stilbenes and Anaphylaxis

Polydatin(PD) shows anti-allergic inflammatory effect, and this study investigated its underlying mechanisms in in vitro and in vivo models. IgE-mediated passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis (PSA) models were used to confirm PD effect in vivo. Various signaling pathway proteins in mast cell were examined. RT-PCR, ELISA and western blotting were applied when appropriate. Activity of Lyn and Fyn kinases in vitro was measured using the Kinase Enzyme System. PD dose-dependently reduced the pigmentation of Evans blue in the PCA model and decreased the concentration of serum histamine in PSA model, and attenuated the degranulation of mast cells without generating cytotoxicity. PD decreased pro-inflammatory cytokine expression (TNF-α, IL-4, IL-1β, and IL-8). PD directly inhibited activity of Lyn and Syk kinases and down-regulated downstream signaling pathway including MAPK, PI3K/AKT and NF-kB. In addition, PD also targets Nrf2/HO-1 pathway to inhibit mast cell-derived allergic inflammatory reactions. In conclusion, the study demonstrates that PD is a possible therapeutic candidate for allergic inflammatory diseases. It directly inhibited activity of Lyn and Syk kinases and down-regulates the signaling pathway of MAPK, PI3K/AKT and NF-κB, and up-regulates the signaling pathway of Nrf2/HO-1 to inhibit the degranulation of mast cells.

Topics: Anaphylaxis; Animals; Cell Degranulation; Cytokines; Dermatitis, Atopic; Extracellular Signal-Regulated MAP Kinases; Glucosides; Heme Oxygenase-1; Inflammation; Male; MAP Kinase Signaling System; Mast Cells; Membrane Proteins; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Stilbenes

Piceatannol is a phenolic stilbenoid and a metabolite of resveratrol which is found in red wine. Piceatannol (PIC) commonly exhibits anti-inflammatory, antiplatelet and antiproliferative activity. In the present study, the anti-allergic and anti-inflammatory mechanisms of PIC were investigated by examining the effects of PIC on pro‑inflammatory cytokine release and phosphorylation of mitogen-activated protein (MAP) kinases (ERK, JNK and p38) in a human mast cell line. PIC dose-dependently inhibited compound 48/80-induced systemic anaphylaxis and immunoglobulin E-mediated local allergic reactions. PIC reduced the immunoglobulin E (IgE)-mediated local allergic reaction and attenuated histamine release from rat peritoneal mast cells. Histamine and β-hexosaminidase release was markedly decreased dose-dependently by PIC treatment in RBL-2H3 cells. PIC treatments of HMC-1 cells definitely reduced mRNA expression and the release of the pro‑inflammatory cytokines, tumor necrosis factor-α and interleukin-8. MAP kinase phosphorylation was also strongly decreased dose-dependently following PIC treatment. PIC regulated the production of cytokines and histamine in phorbol 12-myristate 13-acetate plus A23187-stimulated mast cells. Thus, PIC may alleviate allergic inflammation and may be a useful therapeutic agent for allergic diseases.

Topics: Anaphylaxis; Animals; Anti-Inflammatory Agents; beta-N-Acetylhexosaminidases; Cell Line; Cell Survival; Cytokines; Extracellular Signal-Regulated MAP Kinases; Histamine; Humans; Male; Mast Cells; Mice; Mice, Inbred ICR; p-Methoxy-N-methylphenethylamine; Signal Transduction; Stilbenes

Resveratrol is a phytoalexin abundantly found in red grape skin and is effective in antitumor and antiinflammation associated with immune responses. This study investigated whether resveratrol suppressed immunoglobulin (Ig)E-mediated allergic responses and passive cutaneous anaphylaxis (PCA) in rat RBL-2H3 mast cells and in BALB/c mice. The release of β-hexosaminidase and histamine was enhanced in mast cells sensitized with anti-dinitrophenyl (DNP)-IgE and subsequently stimulated by DNP-human serum albumin (HSA), indicative of mast cell degranulation. When mast cells were pretreated with nontoxic resveratrol at 1-25 μmol/L, such induction was dose dependently diminished. Spleen tyrosine kinase (Syk) and phospholipase Cγ (PLCγ) of sensitized mast cells were activated by stimulation with DNP-HSA antigen, which was dampened by ≥5 μmol/L resveratrol. The phosphorylation of protein kinase C (PKC)μ and PKCθ was attenuated by administering resveratrol to DNP-HSA-exposed mast cells, whereas quiescent PKCζ/λ in sensitized cells was dose-dependently activated by resveratrol. Male BALB/c mice were sensitized for 24 h with DNP-IgE and orally administered with resveratrol 1 h before the DNP-HSA challenge. The histamine concentration was enhanced in sensitized mice challenged to DNP-HSA, which was reversed by administration of 10 mg/kg resveratrol. Additionally, it encumbered the tissue activation of Syk, PLCγ, and PKCμ in antigen-exposed mice. Resveratrol decreased IgE-mediated PCA and alleviated allergic edema of mouse ear and dorsal skin. Mast cell degranulation and allergic inflammation, accompanying the induction of monocyte chemotactic protein-1 and macrophage inflammatory protein-2, were inhibited by supplementing resveratrol to antigen-challenged mice. Resveratrol inhibited mast cell-derived, immediate-type allergic reactions, and these responses of resveratrol suggest possible therapeutic strategies in preventing allergic inflammatory diseases.

Topics: Anaphylaxis; Animals; Basophils; beta-N-Acetylhexosaminidases; CD24 Antigen; Chemokine CCL2; Chemokine CXCL2; Dietary Supplements; Dinitrophenols; Dose-Response Relationship, Drug; Edema; Histamine; Histamine Release; Immunoglobulin E; Inflammation; Intracellular Signaling Peptides and Proteins; Male; Mast Cells; Mice; Mice, Inbred BALB C; Passive Cutaneous Anaphylaxis; Phospholipase C gamma; Phosphorylation; Phytotherapy; Plant Extracts; Protein-Tyrosine Kinases; Rats; Resveratrol; Serum Albumin; Skin; Stilbenes; Syk Kinase; Vitis

Activation of nontransmembrane protein tyrosine kinases, such as Lyn and Syk, has been shown to be the earliest detectable signaling response to Fc receptor (Fc epsilon RI) cross-linking on mast cells leading to mast cell degranulation. The present study examined the effects of piceatannol (3,4,3',5'-tetrahydroxy-trans-stilbene, 10-100 microM), a Syk-selective tyrosine kinase inhibitor, on ovalbumin-induced anaphylactic contraction of isolated guinea pig bronchi and release of histamine and peptidoleukotrienes from chopped lung preparations. Pretreatment with piceatannol slightly suppressed ovalbumin-induced peak anaphylactic bronchial contraction but markedly (P<0.05) facilitated relaxation of the anaphylactically contracted bronchi. Piceatannol did not inhibit direct histamine-, leukotriene D(4)- or KCl-induced bronchial contraction, nor revert an existing anaphylactic bronchial contraction. Piceatannol, at 30 microM and above, significantly (P<0.05) prevented ovalbumin-induced release of both histamine and peptidoleukotrienes from lung fragments. Piceatannol did not inhibit exogenous arachidonic acid-induced release of peptidoleukotrienes from lung fragments. Our data show for the first time that inhibition of Syk tyrosine kinase can attenuate anaphylactic bronchial contraction in vitro, probably via inhibition of mast cell degranulation.

Topics: Airway Obstruction; Anaphylaxis; Animals; Bronchoconstriction; Enzyme Inhibitors; Enzyme Precursors; Enzyme-Linked Immunosorbent Assay; Guinea Pigs; Histamine Release; In Vitro Techniques; Injections, Intraperitoneal; Intracellular Signaling Peptides and Proteins; Leukotrienes; Lung; Male; Ovalbumin; Protein-Tyrosine Kinases; Stilbenes; Syk Kinase

Topics: Anaphylaxis; Aniline Compounds; Head; Head and Neck Neoplasms; Hemangioma; Humans; Hypersensitivity; Neck; Neoplasms; Stilbenes