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( Seung Lark Hwang ),( Xian Li ),( Yue Lu ),( Ye Jin ),( Yong Tae Jeong ),( Yong Deuk Kim ),( In Kyu Lee ),( Yoshitaka Taketomi ),( Hiroyasu Sato ),( You Sook Cho ),( Makoto Murakami ),( Hyeun Wook Ch 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
Background: Aggregation of FcεRI activates a cascade of signaling events leading to mast cell activation, followed by inhibitory signals that turn off the activating signals. However, the overall view of negative signals in mast cells is still incomplete. Although AMP-activated protein kinase (AMPK), which is generally known as a regulator of energy metabolism, is also associated with anti-inflammation, little is known about the role of AMPK in mast cells. Objectives: We investigated the role of AMPK and its regulatory mechanism in mast cells. Method: The roles of AMPK in FcεRI-dependent activation of bone marrow-derived mast cells (BMMCs) were evaluated by using chemical agents, small interfering RNAs (siRNAs), or adenovirus that modulated the activity or expression of AMPK signaling components. In addition, AMPKα2(-/-) mice were used to verify the role of AMPK in anaphylactic models. Results: FcεRI signaling and associated effector functions in BMMCs were suppressed by the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) and were conversely augmented by siRNA knockdown of AMPKα2 or liver kinase B1 (LKB1), an upstream kinase of AMPK. Furthermore, AMPKα2 deficiency led to increased FcεRI-mediated BMMC activation and anaphylaxis that were insensitive to AICAR, whereas enforced expression of AMPKα2 in AMPKα2(-/-) BMMCs reversed the hypersensitive FcεRI signaling to normal levels. Pharmacologic inhibition or siRNA knockdown of Fyn mimicked AMPK activation, suggesting that Fyn counterregulates the LKB1-AMPK axis. Mechanistically, Fyn controlled AMPK activity by regulating LKB1 localization. Conclusions: The Fyn-regulated LKB1-AMPK axis acts as a novel inhibitory module for mast cell activation, which points to AMPK activators as therapeutic drugs for allergic diseases. (J Allergy Chin Immunol 2013;132: 729-36)
( Yue Lu ),( Ju Hye Yang ),( Xian Li ),( Kyoung Hwang Bo ),( Seung Lark Hwang ),( Yoshitaka Taketomi ),( Makoto Murakami ),( Young Chae Chang ),( Cheorl Ho Kim ),( Jong Keun Son ),( Hycun Wook Chang ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
The high-affinity receptor for IgE (Fc□RI)-mediated activation of mast cells plays an important role in allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. Emodin, a naturally occurring anthraquinone derivative in oriental herbal medicines, has several beneficial pharmacologic effects, such as anti-cancer and anti-diabetic activities. However, the anti-allergic effect of emodin has not yet been investigated. To assess the anti-allergic activity of emodin, in vivo passive anaphylaxis animal model and in vitro mouse bone marrow-derived mast cells were used to investigate the mechanism of its action on mast cells. Our results showed that emodin inhibited degranulation, generation of eicosanoids (prostaglandin D(2) and leukotriene C(4)), and secretion of cytokines (TNF-α and IL-6) in a dose-dependent manner in IgE/Ag-stimulated mast cells. Biochemical analysis of the Fc□RI-mediated signaling pathways demonstrated that emodin inhibited the phosphorylation of Syk and multiple downstream signaling processes including mobilization of intracellular Ca(2+) and activation of the mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and NF-κB pathways. When administered orally, emodin attenuated the mast cell-dependent passive anaphylactic reaction in IgE-sensitized mice. Thus, emodin inhibits mast cell activation and thereby the anaphylactic reaction through suppression of the receptor-proximal Syk-dependent signaling pathways. Therefore, emodin might provide a basis for development of a novel anti-allergic drug.
Hwang, Seung-Lark,Li, Xian,Lu, Yue,Jin, Ye,Jeong, Yong-Tae,Kim, Yong Deuk,Lee, In-Kyu,Taketomi, Yoshitaka,Sato, Hiroyasu,Cho, You Sook,Murakami, Makoto,Chang, Hyeun Wook Elsevier 2013 The Journal of allergy and clinical immunology Vol.132 No.3
<P><B>Background</B></P> <P>Aggregation of FcεRI activates a cascade of signaling events leading to mast cell activation, followed by inhibitory signals that turn off the activating signals. However, the overall view of negative signals in mast cells is still incomplete. Although AMP-activated protein kinase (AMPK), which is generally known as a regulator of energy metabolism, is also associated with anti-inflammation, little is known about the role of AMPK in mast cells.</P> <P><B>Objectives</B></P> <P>We investigated the role of AMPK and its regulatory mechanism in mast cells.</P> <P><B>Method</B></P> <P>The roles of AMPK in FcεRI-dependent activation of bone marrow–derived mast cells (BMMCs) were evaluated by using chemical agents, small interfering RNAs (siRNAs), or adenovirus that modulated the activity or expression of AMPK signaling components. In addition, <I>AMPKα2</I> <SUP>−/−</SUP> mice were used to verify the role of AMPK in anaphylactic models.</P> <P><B>Results</B></P> <P>FcεRI signaling and associated effector functions in BMMCs were suppressed by the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) and were conversely augmented by siRNA knockdown of AMPKα2 or liver kinase B1 (LKB1), an upstream kinase of AMPK. Furthermore, <I>AMPKα2</I> deficiency led to increased FcεRI-mediated BMMC activation and anaphylaxis that were insensitive to AICAR, whereas enforced expression of AMPKα2 in <I>AMPKα2</I> <SUP>−/−</SUP> BMMCs reversed the hypersensitive FcεRI signaling to normal levels. Pharmacologic inhibition or siRNA knockdown of Fyn mimicked AMPK activation, suggesting that Fyn counterregulates the LKB1-AMPK axis. Mechanistically, Fyn controlled AMPK activity by regulating LKB1 localization.</P> <P><B>Conclusions</B></P> <P>The Fyn-regulated LKB1-AMPK axis acts as a novel inhibitory module for mast cell activation, which points to AMPK activators as therapeutic drugs for allergic diseases.</P>
( Seung Lark Hwang ),( Yue Lu ),( Xian Li Msc ),( Yong Deuk Kim ),( You Sook Cho ),( Yurn Dong Jahng ),( Jong Keun Son ),( Youn Ju Lee ),( Won Ku Kang ),( Yoshitaka Taketomi ),( Makoto Murakami ),( Ta 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-
Background: Extracellular signal-regulated kinases 1/2 (ERK1/2) make important contributions to allergic responses via their regulation of degranulation, eicosanoid production, and cytokine expression by mast cells, yet the mechanisms underlying their positive effects on FcεRI-dependent signaling are not fully understood. Recently, we reported that mast cell activation and anaphylaxis are negatively regulated by AMP-activated protein kinase (AMPK). However, little is known about the relationship between ERK1/2-mediated positive and the AMPK-mediated negative regulation of FcεRI signaling in mast cells. Objective: We investigated possible interactions between ERK1/2 and AMPK in the modulation of mast cell signaling and anaphylaxis. Methods: Wild-type or AMPKa22/2 mice, or bone marrow. derived mast cells obtained from these mice, were treated with either chemical agents or small interfering RNAs that modulated the activity or expression of ERK1/2 or AMPK to evaluate the functional interplay between ERK1/2 and AMPK in FcεRI-dependent signaling. Results: The ERK1/2 pathway inhibitor U0126 and the AMPK activator 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside similarly inhibited FcεRI-mediated mast cell signals in vitro and anaphylaxis in vivo. ERK1/2-specific small interfering RNA also mimicked this effect on FcεRI signals. Moreover, AMPKa2 knockdown or deficiency led to increased FcεRI-mediated mast cell activation and anaphylaxis that were insensitive to U0126 or activator 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside, suggesting that the suppression of FcεRI signals by the inhibition of the ERK1/2 pathway relies largely on AMPK activation. ERK1/2 controlled AMPK activity by regulating its subcellular translocation. Conclusions: ERK1/2 ablated the AMPK-dependent negative regulatory axis, thereby activating FcεRI signals in mast cells. (J Allergy Clin Immunol 2014;134:714-21.)