12 research outputs found
Interferon-α and Interleukin-12 Are Induced Differentially by Toll-like Receptor 7 Ligands in Human Blood Dendritic Cell Subsets
Dendritic cells (DCs) play a crucial role in the immune responses against infections by sensing microbial invasion through toll-like receptors (TLRs). In humans, two distinct DC subsets, CD11c− plasmacytoid DCs (PDCs) and CD11c+ myeloid DCs (MDCs), have been identified and can respond to different TLR ligands, depending on the differential expression of cognate TLRs. In this study, we have examined the effect of TLR-7 ligands on human DC subsets. Both subsets expressed TLR-7 and could respond to TLR-7 ligands, which enhanced the survival of the subsets and upregulated the surface expression of costimulatory molecules such as CD40, CD80, and CD86. However, the cytokine induction pattern was distinct in that PDCs and MDCs produced interferon (IFN)-α and interleukin (IL)-12, respectively. In response to TLR-7 ligands, the Th1 cell supporting ability of both DC subsets was enhanced, depending on the cytokines the respective subsets produced. This study demonstrates that TLR-7 exerts its biological effect in a DC subset-specific manner
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Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α+ DC correlates with unresponsiveness to imidazoquinolines
Toll-like receptors (TLR) recognize microbial and viral patterns and activate dendritic cells (DC). TLR distribution among human DC subsets is heterogeneous: plasmacytoid DC (PDC) express TLR1, 7 and 9, while other DC types do not express TLR9 but express other TLR. Here, we report that mRNA for most TLR is expressed at similar levels by murine splenic DC sub-types, including PDC, but that TLR3 is preferentially expressed by CD8α+ DC while TLR5 and TLR7 are selectively absent from the same subset. Consistent with the latter, TLR7 ligand activates CD8α– DC and PDC, but not CD8α+ DC as measured by survival ex vivo, up-regulation of surface markers and production of IL-12p40. These data suggest that the dichotomy in TLR expression between plasmacytoid and non-plasmacytoid DC is not conserved between species. However, lack of TLR7 expression could restrict the involvement of CD8α+ DC in recognition of certain mouse pathogens
Dihydropyrrolo[2,3‑<i>d</i>]pyrimidines: Selective Toll-Like Receptor 9 Antagonists from Scaffold Morphing Efforts
Toll-like receptors (TLRs) play important
roles in the innate immune
system. In fact, recognition of endogenous immune complexes containing
self-nucleic acids as pathogen- or damage-associated molecular patterns
contributes to certain autoimmune diseases, and inhibition of these
recognition signals is expected to have therapeutic value. We identified
dihydropyrrolo[2,3-<i>d</i>]pyrimidines as novel selective
TLR9 antagonists with high aqueous solubility. A structure–activity
relationship study of a known TLR9 antagonist led to the promising
compound <b>18</b>, which showed potent TLR9 antagonistic activity,
sufficient aqueous solubility for parenteral formulation, and druggable
properties. Compound <b>18</b> suppressed the production of
the proinflammatory cytokine IL-6 in CpG-induced mouse model. It is
therefore believed that compound <b>18</b> has great potential
in the treatment of TLR9-mediated systemic uncontrollable inflammatory
response like sepsis
Discovery of a Highly Specific Anti-methotrexate (MTX) DNA Aptamer for Antibody-Independent MTX Detection
High-dose methotrexate (MTX) therapy
is used to treat a wide variety
of cancers such as leukemia and lymphoma, while the resulting high
blood concentration of MTX faces a risk of life-threatening side effects,
so it is essential to monitor the concentration carefully. Currently,
the MTX concentration is measured using antibody-based kits in a clinical
setting; however, the heterogeneity and batch-to-batch variation of
antibodies potentially compromise the detection limit. Here, we developed
MTX detection systems with chemically synthesizable homogeneous oligonucleotides.
Microbead-assisted capillary electrophoresis (MACE)-SELEX against
MTX successfully identified MSmt7 with a similar level
of specificity to anti-MTX antibodies within three rounds. The 3′-end
of MSmt7 was coupled to a peroxidase-like hemin-DNAzyme
to construct a bifunctional oligonucleotide for MTX sensing, where
MTX in 50% human serum was detected with a limit of detection (LoD)
of 118 nM. Furthermore, amplifying the DNAzyme region with rolling
circle amplification significantly improved the sensitivity with an
LoD of 290 pM. Presented oligonucleotide-based MTX detection systems
will pave the way for antibody-independent MTX detection with reliability
and less cost in the laboratory and the clinic