title: Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod.
abstract: The immune response modifiers, imiquimod and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and resiquimod. Results indicate that imiquimod and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. Resiquimod enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. Resiquimod was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability.
authors.affiliation: Department of Pharmacology, 3M Pharmaceuticals, 3M Center, 270-2S-06, St. Paul, MN 55144-1000, USA.
authors.forename: Sheila J
authors.initials: SJ
authors.lastname: Gibson
authors.forename: Jana M
authors.initials: JM
authors.lastname: Lindh
authors.forename: Tony R
authors.initials: TR
authors.lastname: Riter
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Gleason
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rogers
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Fuller
authors.forename: JoAnn L
authors.initials: JL
authors.lastname: Oesterich
authors.forename: Keith B
authors.initials: KB
authors.lastname: Gorden
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Qiu
authors.forename: Scott W
authors.initials: SW
authors.lastname: McKane
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Noelle
authors.forename: Richard L
authors.initials: RL
authors.lastname: Miller
authors.forename: Ross M
authors.initials: RM
authors.lastname: Kedl
authors.forename: Patricia
authors.initials: P
authors.lastname: Fitzgerald-Bocarsly
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tomai
authors.forename: John P
authors.initials: JP
authors.lastname: Vasilakos
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000634:Aminoquinolines / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000145:classification / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D029721:Drosophila Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D000077271:Imiquimod; D007369:Interferon Inducers / Q000494:pharmacology*; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D007377:Interleukin-3 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D054400:Receptors, CCR7; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000502:physiology; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; C515370:CCR7 protein, human; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D029721:Drosophila Proteins; D007093:Imidazoles; D007369:Interferon Inducers; D007370:Interferon Type I; D016898:Interferon-alpha; D007377:Interleukin-3; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D054400:Receptors, CCR7; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C063743:interferon omega 1; D000077271:Imiquimod; C402365:resiquimod