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

被引：53

作者：

Hirata, Noriyuki ^{[1
]}

Yanagawa, Yoshiki ^{[1
]}

Ebihara, Takashi ^{[2
]}

Seya, Tsukasa ^{[2
]}

Uematsu, Satoshi ^{[3
]}

Akira, Shizuo ^{[3
]}

Hayashi, Fumie ^{[1
]}

Iwabuchi, Kazuya ^{[1
]}

Onoe, Kazunori ^{[1
]}

机构：

[1] Hokkaido Univ, Div Immunobiol, Inst Med Genet, Kita Ku, Sapporo, Hokkaido 0600815, Japan

[2] Hokkaido Univ, Dept Microbiol & Immunol, Grad Sch Med, Sapporo, Hokkaido 0600815, Japan

[3] Osaka Univ, Dept Host Def, Res Inst Microbial Dis, Osaka, Japan

来源：

MOLECULAR IMMUNOLOGY | 2008年 / 45卷 / 10期

关键词：

dendritic cells; toll-like receptor; cytokines; signal transduction;

D O I：

10.1016/j.molimm.2008.02.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 LIPS, 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. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：2734 / 2742

页数：9

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