title: Inhibitory effects of parthenolide on antigen-induced microtubule formation and degranulation in mast cells.
abstract: Pharmacological modulation of IgE-mediated mast cell activation is important to the development of anti-allergic reagents. In this study, we investigated the effects of parthenolide (PTL) on high-affinity IgE receptor (FcepsilonRI)-induced degranulation in mast cells. PTL dose-dependently inhibited degranulation induced by IgE.antigen stimulation in RBL-2H3 cells and BMMCs. Although PTL is a potent NF-kappaB inhibitor by targeting IkappaB kinase complex, NF-kappaB inhibition by other IkappaB kinase inhibitors did not inhibit degranulation in mast cells. IgE.antigen-induced microtubule formation is well known to be critical for degranulation in mast cells. Immunocytochemical study with anti-alpha-tubulin antibody revealed that PTL significantly inhibited IgE.antigen-induced microtubule formation. However, PTL, as well as nocodazol, had no significant effects on degranulation in the fyn-deficient BMMCs, suggesting that inhibitory effects of PTL in the microtubule formation are fyn dependent. We further demonstrated that in vivo administration of PTL in mice strongly inhibited passive cutaneous anaphylaxis reaction. The present study provides a possibility to develop potent reagents against mast cell activation based on an inhibition of microtubule formation.
authors.affiliation: Division of Molecular Cell Immunology and Allergology, Department of Advanced Medical Research Center, Nihon University School of Medicine, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Miyata
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Gon
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nunomura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Endo
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yamashita
authors.forename: Ken
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Shu
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015550:Cell Degranulation; D002460:Cell Line; D002478:Cells, Cultured; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology*; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects / Q000276:immunology; D017455:Receptors, IgE / Q000276:immunology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D017455:Receptors, IgE; D012717:Sesquiterpenes; D050257:Tubulin Modulators; C002669:parthenolide; D007073:Immunoglobulin E; D051550:I-kappa B Kinase; D015739:Nocodazole