Celastrol binds to ERK and inhibits FcepsilonRI signaling to exert an anti-allergic effect.
The role of celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," in allergic inflammation was investigated. Celastrol decreased the secretion of beta-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 (FcepsilonRIgamma) and ERK and inhibited interaction between FcepsilonRIgamma and protein kinase C delta (PKCdelta). Antigen stimulation induced an interaction between Rac1 and ERK as well as an interaction between Rac1 and PKCdelta. 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 PKCalpha, PKCdelta, and Rac1 in antigen-stimulated RBL2H3 cells. Exposure to celatrol inhibited PKCdelta activity in antigen-stimulated RBL2H3 cells. Celastrol exerted a negative effect on FcepsilonRIbeta signaling by inhibiting the interaction between heat shock protein 90 (hsp90) and proteins, such as, FcepsilonRIbeta, Akt and PKCalpha. 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 FcepsilonRI signaling to exert an anti-inflammatory effect.
School of Biological Sciences, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Republic of Korea.
Youngmi
Y
Kim
Kyungjong
K
Kim
Hansoo
H
Lee
Sanghwa
S
Han
Yun-Sil
YS
Lee
Jongseon
J
Choe
Young-Myeong
YM
Kim
Jang-Hee
JH
Hahn
Jai Youl
JY
Ro
Dooil
D
Jeoung
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006636:Histamine Release / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D053978:Pentacyclic Triterpenes; D051381:Rats; D017455:Receptors, IgE / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D014315:Triterpenes / Q000494:pharmacology*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors
D018926:Anti-Allergic Agents; C521907:Fc-epsilon receptor I beta-chain, mouse; D053978:Pentacyclic Triterpenes; D017455:Receptors, IgE; D014315:Triterpenes; D048049:Extracellular Signal-Regulated MAP Kinases; D001619:beta-N-Acetylhexosaminidases; C050414:celastrol; D002118:Calcium