Toll-like Receptor 2 (TLR2) and TLR4 Differentially Activate Human Dendritic Cells*

By F. Re, J. Strominger. Journal of Biological Chemistry, 2001

756 citations recorded by the source corpus.

Toll-like receptors (TLRs) mediate cell activation by various microbial products. Here, we demonstrate that activation of dendritic cells by TLR2 or TLR4 agonists, although it led to comparable activation of NF-κB and mitogen-activated protein kinase (MAPK) family members, resulted in striking differences in cytokine and chemokine gene transcription, suggesting that TLR2 and TLR4 signaling is not equivalent. A TLR4 agonist specifically promoted the production of the Th1-inducing cytokine interleukin (IL) 12 p70 and the chemokine interferon-γ inducible protein (IP)-10, which is also associated to Th1 responses. In contrast, TLR2 stimulation failed to induce IL-12 p70 and interferon-γ inducible protein (IP)-10 but resulted in the release of the IL-12 inhibitory p40 homodimer, producing conditions that are predicted to favor Th2 development. TLR2 stimulation also resulted in preferential induction of IL-8 and p19/IL-23. Involvement of phosphatidylinositol 3-kinase and p38 MAPK in the TLR-mediated induction of several cytokine and chemokine messages was demonstrated using specific inhibitors. Thus, TLRs can translate the information regarding the nature of pathogens into differences in the cytokines and chemokines produced by dendritic cells and therefore may contribute to the polarization of the acquired immune response.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/3066fe49b01e9e9c1838dd46385ae4e567632d5c

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In Immunology

1. D. Cua
2. Shizuo Akira
3. Luke A. O'Neill
4. V. Kuchroo
5. K. Takeda
6. T. Kaisho
7. M. Kapsenberg
8. T. Korn

Citations in the corpus

• IL‐12 and IL‐23: master regulators of innate and adaptive immunity (2004, background): “Murine IL-23R was detected on activated T cells, bone marrow-derived DCs, macrophages activated with lipopolysaccharide (LPS) (12), and inflamma- tory macrophages and microglia infiltrating the central ner- vous system (CNS) during autoimmune inflammation (13).”
• The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense (2000, background): “homodimers, which inhibit the production of active IL-12 (104).”
• A Comparative Review of Toll-Like Receptor 4 Expression and Functionality in Different Animal Species (2014, background): “In porcine blood mononuclear cells, LPS induces or up-regulates the transcription of TLR4, CD14, and MD-2 mRNAs, as well as cytokine mRNAs such as IL-1, IL-10, IL-12, TNF-α, and IFN-γ.”
• An integrated model of the recognition of Candida albicans by the innate immune system (2008, background): “Moreover, TLR2 ligands fail to induce the release of IL-12 and T H 1-type IFNγ, thus promoting conditions that are favourable for T H 2 - or regulatory T cell (T Reg )-type response”
• Toll-like receptors. (2003, background): “Stimulation of dendritic cells with TLR2 and TLR4 agonists induces mRNA expression for distinct types of cytokines and chemokines (222).”
• Dendritic-cell control of pathogen-driven T-cell polarization (2003, background): “This finding is supported by a study showing that TLR2 stimulation by various ligands, but not TLR4 ligation by LPS, induced the expression of messenger RNA encoding the p40 and p19 subunits of the T H 1-cell-polarizing factor IL-23, but failed to induce mRNA expression of the crucial p35 subunit of”
• IL-17 and Th17 Cells. (2009, background): “Whereas TLR4 stimulation by LPS induces p19, p35, and p40—thus producing both functional IL-12p70 and IL-23—stimulation of TLR2 by peptidoglycan induces large amounts of IL-23 but not p35 (100).”
• Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. (2009, background): “In concordance with observations on human Th17 cells, C. albicans hyphae rather than the yeast form preferentially elicited IL-17 production from gd T cells via enhancement of IL-23 production by dendritic cells (DCs) (Acosta-Rodriguez et al., 2007).”
• TLR4, but not TLR2, mediates IFN-β–induced STAT1α/β-dependent gene expression in macrophages (2002, result): “These findings have been supported by the analysis of gene expression patterns and NO release by macrophages and dendritic cells using additional TLR2 agonist”
• Resolution of a chronic viral infection after interleukin-10 receptor blockade (2006, background): “Thus, stronger binding of LCMV clone 13 to TLR2, as opposed to weaker TLR2 binding by LCMV Armstrong (54), could not only induce preferential production of IL-10 by DCs but also inhibit the secretion of cytokines that promote DC diff erentiation, maturation, and proliferation rather than survival (4”