title: Modulation of anti-IgM-induced B cell apoptosis by Bcl-xL and CD40 in WEHI-231 cells. Dissociation from cell cycle arrest and dependence on the avidity of the antibody-IgM receptor interaction.
abstract: The demise of B cell progenitors expressing functional IgM receptors for self appears to be the main mechanism by which B cell tolerance is accomplished. The genetic mechanisms that regulate the death process during this critical step of B cell development are still poorly understood. We have studied the regulation of apoptosis in WEHI-231 lymphoma cells after treatment with a panel of anti-IgM mAbs as an in vitro model of clonal B cell deletion. We showed that a product of bcl-x, Bcl-xL, can inhibit anti-IgM-induced apoptosis but not cell cycle arrest in a dose-dependent manner. Bcl-xL was efficient in protecting B cells from low but not high avidity anti-IgM mAbs. In contrast to that observed with Bcl-xL, CD40 stimulation was efficient in inhibiting both cell cycle arrest and apoptosis after IgM cross-linking regardless of the binding avidity of the anti-IgM Ab. Moreover, activation through IgM receptors but not CD40 induced up-regulation followed by rapid down-modulation of Bcl-xL. Thus, the capacity of Bcl-xL to modulate anti-IgM-induced apoptosis in WEHI-231 cells is highly dependent on the avidity of the Ab-IgM receptor interaction.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
authors.forename: R
authors.initials: R
authors.lastname: Merino
authors.forename: D A
authors.initials: DA
authors.lastname: Grillot
authors.forename: P L
authors.initials: PL
authors.lastname: Simonian
authors.forename: S
authors.initials: S
authors.lastname: Muthukkumar
authors.forename: W C
authors.initials: WC
authors.lastname: Fanslow
authors.forename: S
authors.initials: S
authors.lastname: Bondada
authors.forename: G
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000378:metabolism*; D000915:Antibody Affinity / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000502:physiology*; D002453:Cell Cycle / Q000276:immunology; D007127:Immunoglobulin Constant Regions / Q000032:analysis; D007075:Immunoglobulin M / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D011961:Receptors, Fc / Q000187:drug effects; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
chemical_list: D000888:Antibodies, Anti-Idiotypic; C494812:Bcl2l1 protein, mouse; D019013:CD40 Antigens; D007127:Immunoglobulin Constant Regions; D007075:Immunoglobulin M; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011961:Receptors, Fc; C044203:anti-IgM; D051020:bcl-X Protein