T cell-independent, TLR-induced IL-12p70 production in primary human monocytes.
IL-12p70 is a key cytokine for the induction of Th1 immune responses. IL-12p70 production in myeloid cells is thought to be strictly controlled by T cell help. In this work we demonstrate that primary human monocytes can produce IL-12p70 in the absence of T cell help. We show that human monocytes express TLR4 and TLR8 but lack TLR3 and TLR7 even after preincubation with type I IFN. Simultaneous stimulation of TLR4 and TLR8 induced IL-12p70 in primary human monocytes. IL-12p70 production in peripheral blood myeloid dendritic cells required combined stimulation of TLR7/8 ligands together with TLR4 or with TLR3 ligands. In the presence of T cell-derived IL-4, but not IFN-gamma, stimulation with TLR7/8 ligands was sufficient to stimulate IL-12p70 production. In monocytes, type I IFN was required but not sufficient to costimulate IL-12p70 induction by TLR8 ligation. Furthermore, TLR8 ligation inhibited LPS-induced IL-10 in monocytes, and LPS alone gained the ability to stimulate IL-12p70 in monocytes when the IL-10 receptor was blocked. Together, these results demonstrate that monocytes are licensed to synthesize IL-12p70 through type I IFN provided via the Toll/IL-1R domain-containing adaptor inducing IFN-beta pathway and the inhibition of IL-10, both provided by combined stimulation with TLR4 and TLR8 ligands, triggering a potent Th1 response before T cell help is established.
Bekeredjian-Ding
Isabelle
I
Department of Internal Medicine, Division of Clinical Pharmacology, University of Munich, Germany.
Roth
Susanne Ilona
SI
Gilles
Stefanie
S
Giese
Thomas
T
Ablasser
Andrea
A
Hornung
Veit
V
Endres
Stefan
S
Hartmann
Gunther
G
D000328:Adult; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis*; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D021122:Protein Subunits / Q000096:biosynthesis*; D017452:Receptors, IgG / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000096:biosynthesis / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology*
D007093:Imidazoles; D008024:Ligands; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D021122:Protein Subunits; D017452:Receptors, IgG; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors; D016753:Interleukin-10; D018664:Interleukin-12; C402365:resiquimod