Blockade of TLR9 agonist-induced type I interferons promotes inflammatory cytokine IFN-gamma and IL-17 secretion by activated human PBMC.
Type I interferons (IFN) (IFN-alpha/beta) are recognized as both inhibitors and effectors of autoimmune disease. In multiple sclerosis, IFN-beta therapy appears beneficial, in part, due to its suppression of autoimmune inflammatory Th cell responses. In contrast, in systemic lupus erythematosus (SLE) triggering of plasmacytoid DC (pDC) Toll-like receptors (TLRs) by autoimmune complexes (autoICs) results in circulating type I IFN that appear to promote disease by driving autoantigen presentation and autoantibody production. To investigate how pDC-derived type I IFN might regulate Th cells in SLE, we examined a model in which sustained pDC stimulation by autoICs is mimicked by pretreating normal human PBMC with TLR9 agonist, CpG-A. Subsequently, PBMC Th cells are activated with superantigen, and APC are activated with CD40L. The role of CpG-A/TLR9-induced type I IFN in regulating PBMC is determined by blocking with virus-derived soluble type I IFN receptor, B18R. In summary, pretreatment with either rhIFN-alpha/beta or CpG-A inhibits PBMC secretion of superantigen-induced IFN-gamma and IL-17, and CD40L-induced IL-12p70 and IL-23. B18R prevents these effects. Data indicate that CpG-A-induced type I IFN inhibit IL-12p70-dependent PBMC IFN-gamma secretion by enhancing IL-10. Our results suggest that in SLE, circulating type I IFN may potentially act to inhibit inflammatory cytokine secretion.
Meyers
John A
JA
Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA.
Mangini
Alyson J
AJ
Nagai
Taro
T
Roff
Calvin F
CF
Sehy
David
D
van Seventer
Gijs A
GA
van Seventer
Jean Maguire
JM
D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology / Q000494:pharmacology; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018448:Models, Immunological; D009103:Multiple Sclerosis / Q000178:diet therapy / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology*; D018089:Superantigens / Q000276:immunology / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000276:immunology
D001324:Autoantigens; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D018089:Superantigens; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D023201:CD40 Ligand