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Multiple signaling pathways contribute to synergistic TLR ligand‐dependent cytokine gene expression in human monocyte‐derived macrophages and dendritic cells
Author(s) -
Mäkelä Sanna M.,
Strengell Mari,
Pietilä Taija E.,
Österlund Pamela,
Julkunen Ilkka
Publication year - 2009
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0808503
Subject(s) - tlr3 , biology , microbiology and biotechnology , proinflammatory cytokine , tlr4 , cytokine , tlr7 , signal transduction , monocyte , innate immune system , toll like receptor , immune system , immunology , inflammation
TLRs are innate immune receptors that recognize pathogen‐associated structures. Binding of ligands to different TLRs can induce the production of proinflammatory cytokines in a synergistic manner. We have analyzed the molecular mechanisms of synergy in TLR ligand‐stimulated human monocyte‐derived macrophages and dendritic cells (moDCs). Stimulation of moDCs with the TLR8 ligand together with the TLR3 or TLR4 ligand led to synergistic IL‐6, IL‐10, IL‐12, and TNF‐α mRNA expression and cytokine production. DNA‐binding assays showed that TLR3 and TLR8 stimulation induced binding of multiple IFN regulatory factor (IRF) and STAT transcription factors to the IL‐12p35 gene promoter IFN‐stimulated response element in moDCs and macrophages but with different binding profiles and kinetics. We also demonstrate that NF‐κB, MAPKs and PI‐3K pathways have an important role in TLR‐induced cytokine gene expression, as pharmacological inhibitors of these signaling pathways inhibited TLR3, TLR4, and TLR8 ligand‐induced cytokine mRNA expression and protein production. Especially, synergistic IL‐12p70 production was abolished completely in NF‐κB, MAPK p38, and PI‐3K inhibitor‐treated moDCs. Our data suggest that TLR‐dependent, synergistic cytokine gene expression results from enhanced activation and cooperation among NF‐κB, IRF, MAPK, PI‐3K, and STAT signaling pathways.