title: Interleukin-12 acts as an adjuvant for humoral immunity through interferon-gamma-dependent and -independent mechanisms.
abstract: Interleukin-12 (IL-12) is a pivotal cytokine that has dramatic effects on cell-mediated immunity. It is now becoming increasingly recognized that IL-12 also strongly controls humoral immunity. We have investigated the mechanism by which IL-12 induces alterations in antibody isotype expression by determining the influence of IL-12 on in vitro immunoglobulin (Ig) production in polyclonally activated murine spleen cell cultures. Cells exposed to IL-12 plus lipopolysaccharide or anti-CD40 monoclonal antibody showed dramatically elevated IgG2a and suppressed IgG1 production compared to cells cultured in the absence of IL-12. IL-12 treatment of spleen cell cultures induced expression of gamma2a germ-line transcripts, consistent with initiation of switch recombination to IgG2a. In addition, exposure of limiting dilution cultures to IL-12 increased IgG2a+ cell precursor frequency. All of the above results were dependent on interferon-gamma (IFN-gamma). However, in the absence of IFN-gamma, IL-12 still had significant effects on Ig secretion. Specifically, IL-12 enhanced IgG1 and IgG2b anti-DNP antibody levels in mice containing specific disruptions in the IFN-gamma gene. Our results suggest that IL-12 induces T helper type 1 and natural killer cells to secrete large amounts of IFN-gamma which then causes B cells to switch to IgG2a and IgG3 production. In addition, IL-12 has direct or indirect effects on B cells that are independent of IFN-gamma. The IFN-gamma-independent effects may include enhancement of Ig expression by post-switched cells.
authors.affiliation: Department of Microbiology and Immunology, Medical College of Ohio, Toledo 43699-0008, USA. dmetzger@vortex.mco.edu
authors.forename: D W
authors.initials: DW
authors.lastname: Metzger
authors.forename: R M
authors.initials: RM
authors.lastname: McNutt
authors.forename: J T
authors.initials: JT
authors.lastname: Collins
authors.forename: J M
authors.initials: JM
authors.lastname: Buchanan
authors.forename: V H
authors.initials: VH
authors.lastname: Van Cleave
authors.forename: W A
authors.initials: WA
authors.lastname: Dunnick
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000917:Antibody Formation; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D018664:Interleukin-12; D007371:Interferon-gamma