title: 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.
authors: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.
authors: Noriyuki
authors: N
authors: Hirata
authors: Yoshiki
authors: Y
authors: Yanagawa
authors: Takashi
authors: T
authors: Ebihara
authors: Tsukasa
authors: T
authors: Seya
authors: Satoshi
authors: S
authors: Uematsu
authors: Shizuo
authors: S
authors: Akira
authors: Fumie
authors: F
authors: Hayashi
authors: Kazuya
authors: K
authors: Iwabuchi
authors: Kazunori
authors: K
authors: Onoé
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D018664:Interleukin-12; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases