Celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-allergic effect

Youngmi Kim; Kyungjong Kim; Hansoo Lee; Sanghwa Han; Yun Sil Lee; Jongseon Choe; Young Myeong Kim; Jang Hee Hahn; Jai Youl Ro; Dooil Jeoung

doi:10.1016/j.ejphar.2009.03.071

Celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-allergic effect

Youngmi Kim, Kyungjong Kim, Hansoo Lee, Sanghwa Han, Yun Sil Lee, Jongseon Choe, Young Myeong Kim, Jang Hee Hahn, Jai Youl Ro, Dooil Jeoung

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

Abstract

The role of celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," in allergic inflammation was investigated. Celastrol decreased the secretion of β-hexosaminidase, decreased the release of histamine, decreased the expression of Th2 cytokines and decreased calcium influx and cell adhesion in antigen-stimulated RBL2H3 cells. Exposure to celastrol decreased the phosphorylation of extracellular regulated kinase (ERK) and the ERK kinase activity was decreased in RBL2H3 cells. A molecular dynamics simulation showed binding of celastrol to a large pocket in ERK2, which serves as the ATP-binding site. Exposure to celastrol inhibited the interaction between immunoglobulin Fc epsilon receptor I (FcεRIγ) and ERK and inhibited interaction between FcεRIγ and protein kinase C δ (PKCδ). Antigen stimulation induced an interaction between Rac1 and ERK as well as an interaction between Rac1 and PKCδ. Inhibition of ERK decreased Rac1 activity and inhibition of Rac1 decreased ERK activity in antigen-stimulated RBL2H3 cells. Celastrol regulated the expression of epithelial-mesenchymal transition (EMT)-related proteins through inhibition of PKCα, PKCδ, and Rac1 in antigen-stimulated RBL2H3 cells. Exposure to celatrol inhibited PKCδ activity in antigen-stimulated RBL2H3 cells. Celastrol exerted a negative effect on FcεRIβ signaling by inhibiting the interaction between heat shock protein 90 (hsp90) and proteins, such as, FcεRIβ, Akt and PKCα. Celastrol exerted a negative effect on in vivo atopic dermatitis induced by 2, 4-dinitrofluorobenzene (DNFB), which requires ERK. Celastrol also showed an inhibitory effect on skin inflammation induced by phorbol myristate acetate (PMA) in Balb/c mice. In summary, celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-inflammatory effect.

Original language	English
Pages (from-to)	131-142
Number of pages	12
Journal	European Journal of Pharmacology
Volume	612
Issue number	1-3
DOIs	https://doi.org/10.1016/j.ejphar.2009.03.071
State	Published - 10 Jun 2009

Bibliographical note

Funding Information:
This work was supported by grants from the Korea Research Foundation (C1001478-01-01 and C1006272-01-01) and Vascular Research Center. This work was also supported by the Regional Innovation Center Program of the Ministry of Commerce, Industry, and Energy.

Keywords

Allergic inflammation
Celastrol
Extracellular regulated kinase
FcεRI
Heat shock protein 90

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10.1016/j.ejphar.2009.03.071

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@article{9bb4756a5484481a96cf38e3c352ea58,

title = "Celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-allergic effect",

abstract = "The role of celastrol, a triterpene extracted from the Chinese {"}Thunder of God Vine,{"} in allergic inflammation was investigated. Celastrol decreased the secretion of β-hexosaminidase, decreased the release of histamine, decreased the expression of Th2 cytokines and decreased calcium influx and cell adhesion in antigen-stimulated RBL2H3 cells. Exposure to celastrol decreased the phosphorylation of extracellular regulated kinase (ERK) and the ERK kinase activity was decreased in RBL2H3 cells. A molecular dynamics simulation showed binding of celastrol to a large pocket in ERK2, which serves as the ATP-binding site. Exposure to celastrol inhibited the interaction between immunoglobulin Fc epsilon receptor I (FcεRIγ) and ERK and inhibited interaction between FcεRIγ and protein kinase C δ (PKCδ). Antigen stimulation induced an interaction between Rac1 and ERK as well as an interaction between Rac1 and PKCδ. Inhibition of ERK decreased Rac1 activity and inhibition of Rac1 decreased ERK activity in antigen-stimulated RBL2H3 cells. Celastrol regulated the expression of epithelial-mesenchymal transition (EMT)-related proteins through inhibition of PKCα, PKCδ, and Rac1 in antigen-stimulated RBL2H3 cells. Exposure to celatrol inhibited PKCδ activity in antigen-stimulated RBL2H3 cells. Celastrol exerted a negative effect on FcεRIβ signaling by inhibiting the interaction between heat shock protein 90 (hsp90) and proteins, such as, FcεRIβ, Akt and PKCα. Celastrol exerted a negative effect on in vivo atopic dermatitis induced by 2, 4-dinitrofluorobenzene (DNFB), which requires ERK. Celastrol also showed an inhibitory effect on skin inflammation induced by phorbol myristate acetate (PMA) in Balb/c mice. In summary, celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-inflammatory effect.",

keywords = "Allergic inflammation, Celastrol, Extracellular regulated kinase, FcεRI, Heat shock protein 90",

author = "Youngmi Kim and Kyungjong Kim and Hansoo Lee and Sanghwa Han and Lee, {Yun Sil} and Jongseon Choe and Kim, {Young Myeong} and Hahn, {Jang Hee} and Ro, {Jai Youl} and Dooil Jeoung",

note = "Funding Information: This work was supported by grants from the Korea Research Foundation (C1001478-01-01 and C1006272-01-01) and Vascular Research Center. This work was also supported by the Regional Innovation Center Program of the Ministry of Commerce, Industry, and Energy.",

year = "2009",

month = jun,

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doi = "10.1016/j.ejphar.2009.03.071",

language = "English",

volume = "612",

pages = "131--142",

journal = "European Journal of Pharmacology",

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TY - JOUR

T1 - Celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-allergic effect

AU - Kim, Youngmi

AU - Kim, Kyungjong

AU - Lee, Hansoo

AU - Han, Sanghwa

AU - Lee, Yun Sil

AU - Choe, Jongseon

AU - Kim, Young Myeong

AU - Hahn, Jang Hee

AU - Ro, Jai Youl

AU - Jeoung, Dooil

N1 - Funding Information: This work was supported by grants from the Korea Research Foundation (C1001478-01-01 and C1006272-01-01) and Vascular Research Center. This work was also supported by the Regional Innovation Center Program of the Ministry of Commerce, Industry, and Energy.

PY - 2009/6/10

Y1 - 2009/6/10

N2 - The role of celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," in allergic inflammation was investigated. Celastrol decreased the secretion of β-hexosaminidase, decreased the release of histamine, decreased the expression of Th2 cytokines and decreased calcium influx and cell adhesion in antigen-stimulated RBL2H3 cells. Exposure to celastrol decreased the phosphorylation of extracellular regulated kinase (ERK) and the ERK kinase activity was decreased in RBL2H3 cells. A molecular dynamics simulation showed binding of celastrol to a large pocket in ERK2, which serves as the ATP-binding site. Exposure to celastrol inhibited the interaction between immunoglobulin Fc epsilon receptor I (FcεRIγ) and ERK and inhibited interaction between FcεRIγ and protein kinase C δ (PKCδ). Antigen stimulation induced an interaction between Rac1 and ERK as well as an interaction between Rac1 and PKCδ. Inhibition of ERK decreased Rac1 activity and inhibition of Rac1 decreased ERK activity in antigen-stimulated RBL2H3 cells. Celastrol regulated the expression of epithelial-mesenchymal transition (EMT)-related proteins through inhibition of PKCα, PKCδ, and Rac1 in antigen-stimulated RBL2H3 cells. Exposure to celatrol inhibited PKCδ activity in antigen-stimulated RBL2H3 cells. Celastrol exerted a negative effect on FcεRIβ signaling by inhibiting the interaction between heat shock protein 90 (hsp90) and proteins, such as, FcεRIβ, Akt and PKCα. Celastrol exerted a negative effect on in vivo atopic dermatitis induced by 2, 4-dinitrofluorobenzene (DNFB), which requires ERK. Celastrol also showed an inhibitory effect on skin inflammation induced by phorbol myristate acetate (PMA) in Balb/c mice. In summary, celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-inflammatory effect.

AB - The role of celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," in allergic inflammation was investigated. Celastrol decreased the secretion of β-hexosaminidase, decreased the release of histamine, decreased the expression of Th2 cytokines and decreased calcium influx and cell adhesion in antigen-stimulated RBL2H3 cells. Exposure to celastrol decreased the phosphorylation of extracellular regulated kinase (ERK) and the ERK kinase activity was decreased in RBL2H3 cells. A molecular dynamics simulation showed binding of celastrol to a large pocket in ERK2, which serves as the ATP-binding site. Exposure to celastrol inhibited the interaction between immunoglobulin Fc epsilon receptor I (FcεRIγ) and ERK and inhibited interaction between FcεRIγ and protein kinase C δ (PKCδ). Antigen stimulation induced an interaction between Rac1 and ERK as well as an interaction between Rac1 and PKCδ. Inhibition of ERK decreased Rac1 activity and inhibition of Rac1 decreased ERK activity in antigen-stimulated RBL2H3 cells. Celastrol regulated the expression of epithelial-mesenchymal transition (EMT)-related proteins through inhibition of PKCα, PKCδ, and Rac1 in antigen-stimulated RBL2H3 cells. Exposure to celatrol inhibited PKCδ activity in antigen-stimulated RBL2H3 cells. Celastrol exerted a negative effect on FcεRIβ signaling by inhibiting the interaction between heat shock protein 90 (hsp90) and proteins, such as, FcεRIβ, Akt and PKCα. Celastrol exerted a negative effect on in vivo atopic dermatitis induced by 2, 4-dinitrofluorobenzene (DNFB), which requires ERK. Celastrol also showed an inhibitory effect on skin inflammation induced by phorbol myristate acetate (PMA) in Balb/c mice. In summary, celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-inflammatory effect.

KW - Allergic inflammation

KW - Celastrol

KW - Extracellular regulated kinase

KW - FcεRI

KW - Heat shock protein 90

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SN - 0014-2999

VL - 612

SP - 131

EP - 142

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 1-3

ER -

Celastrol binds to ERK and inhibits FcεRI signaling to exert an anti-allergic effect

Abstract

Bibliographical note

Keywords

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