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Selective synergy in anti-inflammatory cytokine production upon cooperated signaling via TLR4 and TLR2 in murine conventional dendritic cells.

Abstract

Toll-like receptor (TLR) ligands, i.e. lipopolysaccharide (LPS), induce dendritic cell (DC) production of both inflammatory and anti-inflammatory cytokines including interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, and IL-10. The balance of inflammatory versus anti-inflammatory cytokines appears to be crucial to control immune homeostasis. In the present study, we investigated TLR-mediated regulation of inflammatory versus anti-inflammatory cytokine production using murine bone marrow derived conventional DCs. Standard LPS (sLPS) that contains lipoprotein, a TLR2 ligand, induced vigorous production of both IL-10 and IL-12 p40 by DCs. Highly purified LPS (ultra-pure LPS, upLPS) also induced vigorous production of IL-12 p40, but markedly low IL-10 production. Thus, signal deficiency through TLR2 appeared to result in marked reduction in DC production of IL-10 but not IL-12 p40 upon stimulation with upLPS. To examine this possibility, DCs were stimulated with Pam3CSK4, a synthetic ligand of TLR2, in addition to stimulation with upLPS. It was shown that Pam3CSK4 alone failed to induce IL-10 production. However, Pam3CSK4 synergistically enhanced upLPS-induced DC production of IL-10 but neither IL-12 p40 nor TNF-alpha. Extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK)1/2 in DCs were significantly activated by upLPS stimulation. The upLPS-induced activities of these MAPKs were considerably enhanced by additional stimulation with Pam3CSK4. Blocking either p38 MAPK or JNK1/2 pathway completely inhibited the synergistic enhancement of the IL-10 production by DCs upon upLPS and Pam3CSK4 stimulation. Thus, cooperated stimulation of these MAPKs via TLR4 and TLR2 appeared to induce selective synergy in anti-inflammatory cytokine production by murine conventional DCs.

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  • Authors+Show Affiliations

    ,

    Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.

    , , , , , , ,

    Source

    Molecular immunology 45:10 2008 May pg 2734-42

    MeSH

    Animals
    Anti-Inflammatory Agents
    Biomarkers
    Cell Membrane
    Cells, Cultured
    Dendritic Cells
    Enzyme Activation
    Extracellular Signal-Regulated MAP Kinases
    Interleukin-10
    Interleukin-12
    JNK Mitogen-Activated Protein Kinases
    Ligands
    Lipopolysaccharides
    Mice
    Mitogen-Activated Protein Kinases
    NF-kappa B
    Protein Kinase Inhibitors
    Signal Transduction
    Toll-Like Receptor 2
    Toll-Like Receptor 4
    p38 Mitogen-Activated Protein Kinases

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    18372043

    Citation

    Hirata, Noriyuki, et al. "Selective Synergy in Anti-inflammatory Cytokine Production Upon Cooperated Signaling Via TLR4 and TLR2 in Murine Conventional Dendritic Cells." Molecular Immunology, vol. 45, no. 10, 2008, pp. 2734-42.
    Hirata N, Yanagawa Y, Ebihara T, et al. Selective synergy in anti-inflammatory cytokine production upon cooperated signaling via TLR4 and TLR2 in murine conventional dendritic cells. Mol Immunol. 2008;45(10):2734-42.
    Hirata, N., Yanagawa, Y., Ebihara, T., Seya, T., Uematsu, S., Akira, S., ... Onoé, K. (2008). Selective synergy in anti-inflammatory cytokine production upon cooperated signaling via TLR4 and TLR2 in murine conventional dendritic cells. Molecular Immunology, 45(10), pp. 2734-42. doi:10.1016/j.molimm.2008.02.010.
    Hirata N, et al. Selective Synergy in Anti-inflammatory Cytokine Production Upon Cooperated Signaling Via TLR4 and TLR2 in Murine Conventional Dendritic Cells. Mol Immunol. 2008;45(10):2734-42. PubMed PMID: 18372043.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Selective synergy in anti-inflammatory cytokine production upon cooperated signaling via TLR4 and TLR2 in murine conventional dendritic cells. AU - Hirata,Noriyuki, AU - Yanagawa,Yoshiki, AU - Ebihara,Takashi, AU - Seya,Tsukasa, AU - Uematsu,Satoshi, AU - Akira,Shizuo, AU - Hayashi,Fumie, AU - Iwabuchi,Kazuya, AU - Onoé,Kazunori, Y1 - 2008/03/26/ PY - 2007/12/26/received PY - 2008/02/13/accepted PY - 2008/3/29/pubmed PY - 2008/7/3/medline PY - 2008/3/29/entrez SP - 2734 EP - 42 JF - Molecular immunology JO - Mol. Immunol. VL - 45 IS - 10 N2 - Toll-like receptor (TLR) ligands, i.e. lipopolysaccharide (LPS), induce dendritic cell (DC) production of both inflammatory and anti-inflammatory cytokines including interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, and IL-10. The balance of inflammatory versus anti-inflammatory cytokines appears to be crucial to control immune homeostasis. In the present study, we investigated TLR-mediated regulation of inflammatory versus anti-inflammatory cytokine production using murine bone marrow derived conventional DCs. Standard LPS (sLPS) that contains lipoprotein, a TLR2 ligand, induced vigorous production of both IL-10 and IL-12 p40 by DCs. Highly purified LPS (ultra-pure LPS, upLPS) also induced vigorous production of IL-12 p40, but markedly low IL-10 production. Thus, signal deficiency through TLR2 appeared to result in marked reduction in DC production of IL-10 but not IL-12 p40 upon stimulation with upLPS. To examine this possibility, DCs were stimulated with Pam3CSK4, a synthetic ligand of TLR2, in addition to stimulation with upLPS. It was shown that Pam3CSK4 alone failed to induce IL-10 production. However, Pam3CSK4 synergistically enhanced upLPS-induced DC production of IL-10 but neither IL-12 p40 nor TNF-alpha. Extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK)1/2 in DCs were significantly activated by upLPS stimulation. The upLPS-induced activities of these MAPKs were considerably enhanced by additional stimulation with Pam3CSK4. Blocking either p38 MAPK or JNK1/2 pathway completely inhibited the synergistic enhancement of the IL-10 production by DCs upon upLPS and Pam3CSK4 stimulation. Thus, cooperated stimulation of these MAPKs via TLR4 and TLR2 appeared to induce selective synergy in anti-inflammatory cytokine production by murine conventional DCs. SN - 0161-5890 UR - https://www.unboundmedicine.com/medline/citation/18372043/Selective_synergy_in_anti_inflammatory_cytokine_production_upon_cooperated_signaling_via_TLR4_and_TLR2_in_murine_conventional_dendritic_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0161-5890(08)00075-8 DB - PRIME DP - Unbound Medicine ER -