title: IL-36-Induced Toxicity in Neonatal Mice Involves TNF-α Production by Liver Myeloid Cells.
abstract: Human and mouse neonates exhibit limited vaccine responses characterized by predominant Th2 and limited Th1 responses. Because IL-36 exerts a synergic adjuvant effect with IL-12, enhancing Th1 polarization in adult (AD) mice, we administered IL-36β to neonatal (1-wk old) and AD control mice at the time of immunization with tetanus toxoid adsorbed to aluminum hydroxide (TT/Alum). Unexpectedly, the combination of IL-36β with TT/Alum, which was well tolerated in AD mice, proved toxic and even lethal in neonates. This neonatal toxicity was associated with high Il36r mRNA expression in neonatal liver, resulting in increased cytokine production. Liver Il36r mRNA expression decreased with the termination of fetal liver hematopoiesis, and this decrease correlated with a complete protection from TT/Alum/IL-36β-induced mortality. The combination of IL-36β and TT/Alum induced the rapid production of TNF-α and IFN-γ by liver myeloid and lymphoid cells, respectively. These responses were less marked when IL-36β was used alone, with no adverse effect. The toxicity of IL-36β + TT/Alum was abrogated by the administration of a neutralizing anti-TNF-α Ab, confirming causality. In conclusion, liver myeloid cells in neonatal mice are an important source of proinflammatory cytokines that may lead to TNF-α-mediated toxicity and even lethality.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, 1211 Geneva 4, Switzerland; Department of Pathology-Immunology, University of Geneva, School of Medicine, 1211 Geneva 4, Switzerland;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Palomo
authors.affiliation: World Health Organization Collaborating Center for Vaccine Immunology, Department of Pathology-Immunology, University of Geneva, School of Medicine, 1211 Geneva 4, Switzerland; and World Health Organization Collaborating Center for Vaccine Immunology, Department of Pediatrics, University of Geneva, School of Medicine, 1211 Geneva 4, Switzerland.
authors.forename: Beatris
authors.initials: B
authors.lastname: Mastelic-Gavillet
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, 1211 Geneva 4, Switzerland; Department of Pathology-Immunology, University of Geneva, School of Medicine, 1211 Geneva 4, Switzerland;
authors.forename: Estelle
authors.initials: E
authors.lastname: Woldt
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, 1211 Geneva 4, Switzerland; Department of Pathology-Immunology, University of Geneva, School of Medicine, 1211 Geneva 4, Switzerland;
authors.forename: Sabina
authors.identifier: 0000-0002-0724-752X
authors.initials: S
authors.lastname: Troccaz
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, 1211 Geneva 4, Switzerland; Department of Pathology-Immunology, University of Geneva, School of Medicine, 1211 Geneva 4, Switzerland;
authors.forename: Emiliana
authors.initials: E
authors.lastname: Rodriguez
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, 1211 Geneva 4, Switzerland; Department of Pathology-Immunology, University of Geneva, School of Medicine, 1211 Geneva 4, Switzerland;
authors.forename: Gaby
authors.initials: G
authors.lastname: Palmer
authors.affiliation: World Health Organization Collaborating Center for Vaccine Immunology, Department of Pathology-Immunology, University of Geneva, School of Medicine, 1211 Geneva 4, Switzerland; and World Health Organization Collaborating Center for Vaccine Immunology, Department of Pediatrics, University of Geneva, School of Medicine, 1211 Geneva 4, Switzerland.
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Siegrist
authors.affiliation: Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, 1211 Geneva 4, Switzerland; Department of Pathology-Immunology, University of Geneva, School of Medicine, 1211 Geneva 4, Switzerland; cem.gabay@hcuge.ch.
authors.forename: Cem
authors.identifier: 0000-0001-6853-3063
authors.initials: C
authors.lastname: Gabay
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000096:biosynthesis; D007375:Interleukin-1 / Q000633:toxicity*; D008099:Liver / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D013745:Tetanus Toxoid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D016207:Cytokines; C502352:IL-1F8 protein, mouse; D007375:Interleukin-1; D013745:Tetanus Toxoid; D014409:Tumor Necrosis Factor-alpha