title: Regulation of Staphylococcus epidermidis-induced IFN-gamma in whole human blood: the role of endogenous IL-18, IL-12, IL-1, and TNF.
abstract: Interleukin 12 (IL-12) and IL-18 act synergistically to stimulate interferon gamma (IFN-gamma) production; moreover, IL-1 and tumor necrosis factor (TNF) may also augment IFN-gamma synthesis. We have investigated the relative contributions of these cytokines in the production of IFN-gamma and TNF by the Gram-positive bacterium Staphylococcus epidermidis, using the specific cytokine inhibitors IL-18 binding protein (IL-18BP), IL-1 receptor antagonist (IL-1Ra), anti-IL-12 antibodies (anti-IL-12 Ab), and TNF binding protein. Inhibition of caspase-1 reduced IFN-gamma and IL-1beta levels (by 80 and 67%, respectively) when heat-killed S. epidermidis was added to whole human blood cultures. IL-18BP reduced S. epidermidis-induced IFN-gamma (77% maximal suppression). In contrast, blocking IL-1 receptors by IL-1Ra had no effect on IFN-gamma production. Blocking endogenous IL-12 and TNF reduced IFN-gamma production by 69 and 36%. S. epidermidis-induced TNF-alpha was inhibited by IL-18BP and IL-1Ra, but not anti-IL-12 Ab, whereas IL-8 production was unaffected by any of the specific cytokine blocking agents. In conclusion, S. epidermidis stimulates IFN-gamma which is IL-18, IL-12 and TNF-dependent, but IL-1 independent.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Rogier J L
authors.initials: RJ
authors.lastname: Stuyt
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Leonid L
authors.initials: LL
authors.lastname: Reznikov
authors.forename: Giamila
authors.initials: G
authors.lastname: Fantuzzi
authors.forename: Daniela
authors.initials: D
authors.lastname: Novick
authors.forename: Menachem
authors.initials: M
authors.lastname: Rubinstein
authors.forename: Bart Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007375:Interleukin-1 / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology*; D020382:Interleukin-18 / Q000502:physiology*; D008875:Middle Aged; D013212:Staphylococcus epidermidis / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D007375:Interleukin-1; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D020170:Caspase 1