title: Distinct modulatory effects of LPS and CpG on IL-18-dependent IFN-gamma synthesis.
abstract: Innate cellular production of IFN-gamma is suppressed after repeated exposure to LPS, whereas CpG-containing DNA potentiates IFN-gamma production. We compared the modulatory effects of LPS and CpG on specific cellular and cytokine responses necessary for NK-cell dependent IFN-gamma synthesis. C3H/HeN mice pretreated with LPS for 2 days generated 5-fold less circulating IL-12 p70 and IFN-gamma in response to subsequent LPS challenge than did challenged control mice. In contrast, CpG-pretreated mice produced 10-fold more circulating IFN-gamma without similar changes in IL-12 p70 levels, but with 10-fold increases in serum IL-18 relative to LPS-challenged control or endotoxin-tolerant mice. The role of IL-18 in CpG-induced immune potentiation was studied in splenocyte cultures from control, LPS-conditioned, or CpG-conditioned mice. These cultures produced similar amounts of IFN-gamma in response to rIL-12 and rIL-18. However, only CpG-conditioned cells produced IFN-gamma when cultured with LPS or CpG, and production was ablated in the presence of anti-IL-18R Ab. Anti-IL-18R Ab also reduced in vivo IFN-gamma production by >2-fold in CpG-pretreated mice. Finally, combined pretreatment of mice with LPS and CpG suppressed the production of circulating IFN-gamma, IL-12 p70, and IL-18 after subsequent LPS challenge. We conclude that CpG potentiates innate IFN-gamma production from NK cells by increasing IL-18 availability, but that the suppressive effects of LPS on innate cellular immunity dominate during combined LPS and CpG pretreatment. Multiple Toll-like receptor engagement in vivo during infection can result in functional polarization of innate immunity dominated by a specific Toll-like receptor response.
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH 41106, USA.
authors.forename: Meetha P
authors.initials: MP
authors.lastname: Gould
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Greene
authors.forename: Vijay
authors.initials: V
authors.lastname: Bhoj
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: DeVecchio
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Heinzel
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000097:blood; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004357:Drug Synergism; D005260:Female; D007111:Immunity, Cellular; D007117:Immunization, Secondary; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000097:blood; D020382:Interleukin-18 / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000097:blood; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000276:immunology; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053724:Receptors, Interleukin-18; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; C508573:Il18r1 protein, mouse; D007166:Immunosuppressive Agents; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D019444:Vaccines, DNA; D007371:Interferon-gamma