Journal of Clinical Toxicology
Open Access
ISSN: 2161-0495
ISSN: 2161-0495
Hyeun Wook Chang, Xian Li and Young Na Park
Yeungnam University, Republic of South Korea
Posters & Accepted Abstracts: J Clinic Toxicol
Crosslinking of Fc�µRI-bound IgE with antigen on mast cells trigger release of various chemical mediators such as histamine, eicosanoids and cytokines which cause allergic-inflammation responses. Previous reports showed that Fyn-regulated LKB1/AMPK axis plays an important a role in shutting down Fc�µRI-dependent mast cell activation and thereby limiting allergic reactions. Resveratrol, a well-known Sirt1 activator showed various beneficial effects on cardiovascular disease, disorder of glucose metabolism but also exhibited antioxidant, anti-inflammatory and anti-allergic properties in vitro and in vivo models. However, the role of resveratrol in regulating mast cell activation in context of Sirt1-LKB1-AMPK pathway has not been well understood. The anti-allergic effects of resveratrol was evaluated using mouse bone marrow-derived mast cells (BMMCs) from AMPK�±2-/- or Sirt1-/- mice, or BMMCs transfected with siRNAs specific for AMPK�±2, Sirt1 or protein tyrosine phosphatase 1B (PTP1B). AMPK�±2-/- and Sirt1-/- mice were used to confirm the anti-allergic effect of resveratrol in passive cutaneous anaphylaxis (PCA). Resveratrol inhibited Fc�µRI-mediated degranulation and production of LTC4, PGD2, TNF-�±, IL-6 and increase of intracellular Ca2+ in a dose dependent manner, but these inhibitory activities were diminished by the siRNA knockdowns of AMPK�±2 or Sirt1. Moreover, secretion of chemical mediators were partially recovered by gene knockout (or knockdown) of Sirt1 and AMPK�±2, which indicated that resveratrol inhibits mast cell activation by Sirt1 dependent and independent pathways. In addition, oral administration of resveratrol dose dependently suppressed anaphylaxis in wild mice, but the enhanced anaphylaxis in gene knockout of Sirt1 or AMPK�±2 mice were less sensitive to resveratrol compared with wild type mice. Furthermore, we also found that resveratrol stimulated the inhibitory Sirt1-LKB1-AMPK axis, with reciprocal suppression of the stimulatory PTP1B/Syk axis, thus potently inhibiting anaphylaxis. In conclusion, resveratrol attenuates Fc�µRI-mediated mast cell signaling through the activation of inhibitory Sirt1-LKB1-AMPK pathway and inhibition of the stimulatory PTP1B/Syk pathway.
Recent Publications:
1. Chang H W et al. (2013) AMP-activated protein kinase negatively regulates Fc�µRI-mediated mast cell signaling and anaphylaxis in mice. J. Allergy Clin. Immunol. 132(3):729-736.
2. Chang H W et al. (2014) ERK1/2 antagonize AMPK-dependent regulation of Fc�µRI-mediated mast cell activation and anaphylaxis. J. Allergy Clin. Immunol. 134(3):714-721.
3. Chang HW et al. (2016) NecroX-5 suppresses IgE/Ag-stimulated anaphylaxis and mast cell activation by regulating the SHP-1-Syk signaling module. Allergy. 71(2):198-209.
Hyeun Wook Chang focuses his research on the investigation of underlying mechanisms for allergy and inflammatory reactions in mast cells and development of new therapies for related various allergic diseases. In recent years, he has published his research results in the Journal of Allergy and Clinical Immunology which provide a basis for novel approaches to clinical intervention in allergic diseases. He has provided evidences that AMP-activated protein kinase (AMPK), an intracellular energy sensor, might be useful for treatment of not only metabolic syndrome but also allergic diseases.
E-mail: hwchang@ynu.ac.kr