title: IFN-gamma is a potent inducer of Ig secretion by sort-purified murine B cells activated through the mIg, but not the CD40, signaling pathway.
abstract: IFN-gamma has been shown to either stimulate or inhibit Ig secretion. No studies have yet addressed the basis for these seemingly conflicting properties nor whether IFN-gamma acted directly at the level of the B cell to mediate its effects. Thus, we studied the ability of IFN-gamma to regulate Ig secretion in sort-purified, resting murine B cells that were >99% Ig+, activated either through membrane Ig using unconjugated or dextran-conjugated anti-IgD antibodies (alphadelta-dex) or through CD40 using soluble or membrane CD40 ligand (CD40L). B cells activated with alphadelta-dex proliferated but do not secrete Ig, even in the presence of IL-1 + IL-2. We demonstrate that IFN-gamma only when added subsequent to B cell stimulation with alphadelta-dex, but not unconjugated anti-IfD antibody, plus IL-1 + IL-2 induces up to 100-fold enhancements in Ig secretion and in the numbers of Ig-secreting cells. The predominant Ig isotype secreted is IgM, with IgG3 and IgG2a comprising the majority of non-IgM antibody. IFN-gamma must act in concert with IL-2 for stimulation of Ig secretion. Further, IFN-gamma synergizes with IL-3 + granulocyte-macrophage colony stimulating factor for induction of Ig synthesis. IFN-gamma also enhances IgA syntheses by transforming growth factor-beta-induced membrane IgA+ cells. By contrast, 125IIFN-gamma fails to stimulate Ig secretion in B cells activated with CD40L in the presence or absence of IL-1 + IL-2 or IL-4. However, the combination of CD40L and alphabeta-dex is strongly synergistic for IFN-gamma-induced Ig secretion. Thus, these data establish that IFN-gamma can act directly on the B cell to induce Ig synthesis without the participation of any other cell and demonstrates that the mode of activation of the B cell plays an important role in directing the action of IFN-gamma.
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Snapper
authors.forename: F
authors.initials: F
authors.lastname: Rosas
authors.forename: M A
authors.initials: MA
authors.lastname: Moorman
authors.forename: L
authors.initials: L
authors.lastname: Jin
authors.forename: K
authors.initials: K
authors.lastname: Shanebeck
authors.forename: D M
authors.initials: DM
authors.lastname: Klinman
authors.forename: M R
authors.initials: MR
authors.lastname: Kehry
authors.forename: J J
authors.initials: JJ
authors.lastname: Mond
authors.forename: C R
authors.initials: CR
authors.lastname: Maliszewski
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D000936:Antigen-Antibody Complex / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects*; D019013:CD40 Antigens / Q000378:metabolism / Q000494:pharmacology*; D023201:CD40 Ligand; D003911:Dextrans / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D007072:Immunoglobulin D / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D011947:Receptors, Antigen, B-Cell / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000936:Antigen-Antibody Complex; D019013:CD40 Antigens; D003911:Dextrans; D007072:Immunoglobulin D; D008562:Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell; D023201:CD40 Ligand; D007371:Interferon-gamma