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Selective synergy in anti-inflammatory cytokine production upon cooperated signaling via TLR4 and TLR2 in murine conventional dendritic cells.
Mol Immunol 2008; 45(10):2734-42MI

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+Show Affiliations

Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -