title: IL-18 and CD28 use distinct molecular mechanisms to enhance NK cell production of IL-12-induced IFN-gamma.
abstract: NK cells play an important role in innate immune resistance, particularly through synthesis of the pro-inflammatory cytokine IFN-gamma. This study compares the abilities of the cytokine IL-18 and the costimulatory cell surface molecule CD28 to enhance IL-12-driven IFN-gamma production by NK cells. Studies with other cytokines (IL-1beta, IL-6, TNF-alpha, IL-15) showed that IL-18 or anti-CD28 treatments were the most efficient inducers of IFN-gamma when combined with IL-12. The ability of IL-18 to enhance IFN-gamma was shown to be dependent on the presence of IL-12. Similarly, although anti-CD28 stimulation alone could enhance IFN-gamma synthesis, this effect was significantly increased in the presence of IL-12. Although neither method of costimulation required de novo protein synthesis for their effects on IFN-gamma mRNA expression, these molecules used distinct mechanisms. Specifically, nuclear run-on analysis revealed that IL-18 in combination with IL-12 enhanced the rate of transcription of the IFN-gamma gene. Conversely, treatment with anti-CD28 plus IL-12 did not significantly up-regulate the rate of transcription of the IFN-gamma gene, but stabilized IFN-gamma mRNA expression within NK cells. These findings illustrate costimulatory pathways that result in potent IFN-gamma responses by NK cells and show that although IL-18 and anti-CD28 can enhance the synthesis of IL-12-driven IFN-gamma, they employ molecular mechanisms that are distinct from one another.
authors.affiliation: Department of Pathobiology, University of Pennsylvania, and The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: W
authors.initials: W
authors.lastname: Walker
authors.forename: M
authors.initials: M
authors.lastname: Aste-Amezaga
authors.forename: R A
authors.initials: RA
authors.lastname: Kastelein
authors.forename: G
authors.initials: G
authors.lastname: Trinchieri
authors.forename: C A
authors.initials: CA
authors.lastname: Hunter
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism*; D004347:Drug Interactions; D018398:Homeodomain Proteins / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D018106:CD28 Antigens; D018398:Homeodomain Proteins; D020382:Interleukin-18; D012333:RNA, Messenger; C064658:RAG-1 protein; D018664:Interleukin-12; D007371:Interferon-gamma