title: Innate immune responses in lupus-prone Palmerston North mice: differential responses to LPS and bacterial DNA/CpG oligonucleotides.
abstract: Inadequate immune response to infectious danger may contribute to the pathogenesis of systemic autoimmune diseases, e.g., systemic lupus erythematosus. To test this hypothesis, we studied innate responses of prediseased lupus-prone Palmerston North (PN) mice to lipopolysaccharide (LPS), bacterial DNA, and synthetic CpG oligonucleotides. LPS and bacterial DNA/CpG oligodeoxyribonucleotides (ODNs) drove PN splenocytes into the cell cycle and protected B cells against spontaneous apoptosis, as in control lupus-free DBA-1 mice. LPS induced significantly higher IL-6 production in PN than in control splenocytes. In contrast, in PN splenocytes bacterial DNA and CpG ODNs induced approximately four- to sixfold lower IL-12p40 and approximately twofold lower IL-6 secretion than controls. This reduction in cytokine secretion in PN mice was not due to delayed kinetics but was related to significantly higher constitutive and CpG-inducible IL-10 secretion. Neutralizing anti-IL-10 antibodies almost completely restored PN IL-6 and IL-12p40 secretion to DBA-1 levels, whereas exogenous IL-10 inhibited in vitro IL-6 and IL-12p40 production in DBA-1 mice. Importantly, treatment with either IL-10 or anti-IL-10 antibody did not modulate CpG-induced cell cycle entry and apoptosis protection in either strain. In conclusion, lupus-prone PN mice show abnormal innate responses through their pattern-recognition TLR9 receptors, characterized by higher inducible IL-10 and lower IL-12p40 and IL-6 secretion, thus implying that response to infectious danger in PN mice is inappropriate and may be linked to lupus pathogenesis.
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA. petar-lenert@uiowa.edu
authors.forename: Petar
authors.initials: P
authors.lastname: Lenert
authors.forename: Adam
authors.initials: A
authors.lastname: Goeken
authors.forename: Barry S
authors.initials: BS
authors.lastname: Handwerger
authors.forename: Robert F
authors.initials: RF
authors.lastname: Ashman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D004269:DNA, Bacterial / Q000276:immunology / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology*; D021122:Protein Subunits / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology; D051217:Toll-Like Receptor 9
chemical_list: D016207:Cytokines; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D021122:Protein Subunits; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D018664:Interleukin-12