title: Diverse effects of eosinophil cationic granule proteins on IMR-32 nerve cell signaling and survival.
abstract: Activated eosinophils release potentially toxic cationic granular proteins, including the major basic proteins (MBP) and eosinophil-derived neurotoxin (EDN). However, in inflammatory conditions including asthma and inflammatory bowel disease, localization of eosinophils to nerves is associated with nerve plasticity, specifically remodeling. In previous in vitro studies, we have shown that eosinophil adhesion to IMR-32 nerve cells, via nerve cell intercellular adhesion molecule-1, results in an adhesion-dependent release of granule proteins. We hypothesized that released eosinophil granule proteins may affect nerve cell signaling and survival, leading to nerve cell remodeling. Culture in serum-deprived media induced apoptosis in IMR-32 cells that was dose-dependently abolished by inclusion of MBP1 but not by EDN. Both MBP1 and EDN induced phosphorylation of Akt, but with divergent time courses and intensities, and survival was independent of Akt. MBP1 induced activation of neural nuclear factor (NF)-kappaB, from 10 min to 12 h, declining by 24 h, whereas EDN induced a short-lived activation of NF-kappaB. MBP1-induced protection was dependent on phosphorylation of ERK 1/2 and was related to a phospho-ERK-dependent upregulation of the NF-kappaB-activated anti-apoptotic gene, Bfl-1. This signaling pathway was not activated by EDN. Thus, MBP1 released from eosinophils at inflammatory sites may regulate peripheral nerve plasticity by inhibiting apoptosis.
authors.affiliation: Department of Medicine, RCSI, Beaumont Hospital, Dublin 9, Ireland, and Department of Dermatology, University of Utah, Salt Lake City, USA.
authors.forename: Ross K
authors.initials: RK
authors.lastname: Morgan
authors.forename: Richard W
authors.initials: RW
authors.lastname: Costello
authors.forename: Niamh
authors.initials: N
authors.lastname: Durcan
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kingham
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Gleich
authors.forename: W Graham
authors.initials: WG
authors.lastname: McLean
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Walsh
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D047093:Eosinophil Major Basic Protein / Q000494:pharmacology*; D047208:Eosinophil-Derived Neurotoxin / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C096816:BCL2-related protein A1; D018076:DNA, Complementary; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D047208:Eosinophil-Derived Neurotoxin; D047093:Eosinophil Major Basic Protein