Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0808503 on January 29, 2009

Published online before print January 29, 2009
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(Journal of Leukocyte Biology. 2009;85:664-672.)
© 2009 by Society for Leukocyte Biology

Multiple signaling pathways contribute to synergistic TLR ligand-dependent cytokine gene expression in human monocyte-derived macrophages and dendritic cells

Sanna M. Mäkelä1, Mari Strengell, Taija E. Pietilä, Pamela Österlund and Ilkka Julkunen

Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland

1 Correspondence: Department of Viral Diseases and Immunology, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. E-mail: sanna.makela{at}ktl.fi

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-{alpha} 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-{kappa}B, 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-{kappa}B, 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-{kappa}B, IRF, MAPK, PI-3K, and STAT signaling pathways.

Key Words: transcription factors • regulation • innate immunity




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