IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases.
IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases.
复制标题
DOI：
10.1371/journal.pone.0107886
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Strippoli R
中科院分区：
文献类型：
--
作者：
Caiello I;Minnone G;Holzinger D;Vogl T;Prencipe G;Manzo A;De Benedetti F;Strippoli R
白细胞介素6(IL-6)在类风湿关节炎(RA)和全身性幼年特发性关节炎(S-JIA)关节和全身炎症的发病机制中的作用已被明确证明。然而，IL-6在发病机制中的作用机制尚不完全清楚。本研究探讨IL-6是否单独或在Toll样受体(TLR)配体刺激下影响人外周血单个核细胞(PBMCs)、JIA患者滑液单个核细胞(SFMCs)和类风湿关节炎患者成纤维样滑膜细胞(RA滑膜细胞)产生炎性细胞因子和趋化因子，以及相关的信号通路。用IL-6和可溶性IL-6受体(sIL-6R)处理PBMC。用IL-6/sIL-6R或sIL-6R单独或联合Tocilizumab(TCZ)处理SFMCs和RA滑膜细胞。用脂多糖、S100A8-9、Poly(I-C)、CpG、Pam2CSK4、MDP、IL-1β刺激细胞。IL-6可诱导PBMC产生肿瘤坏死因子-α、CXCL_8和CCL_2，但不能产生IL-1β。在相同的细胞中加入IL-6后，与单独使用TLR配体相比，Pam2CSK4和MDP能显著增加IL-1β和CXCL8的产生，但不能诱导α的产生。这种增加IL-1β和CXCL8的产生与增加p65 NF-κB的激活是平行的。相反，在脂多糖或S100A8-9(TLR4配体)刺激的PBMC中加入IL-6可降低IL-1β、肿瘤坏死因子-α和CXCL8的表达，同时降低p65-NF-κB的活性。IL-6/IL-1β共刺激可增加CXCL_8、CCL_2和IL-6的产生。在脂多糖或S100A8刺激的SFMC中加入IL-6可增加CXCL_8、CCL_2和IL-1β的产生。SIL-6R处理RA滑膜细胞可增加IL-6、CXCL8和CCL2的产生，并增加STAT3和p65NF-κB的磷酸化。我们的结果表明，IL-6增强了TLR诱导的炎症反应。这种效应可能与高IL-6和sIL-6R水平的存在有关，例如在内源性TLR配体刺激的关节炎关节中。
The role of Interleukin(IL)-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (s-JIA) has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone or upon toll like receptor (TLR) ligand stimulation, the production of inflammatory cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs), synovial fluid mononuclear cells from JIA patients (SFMCs) and fibroblast-like synoviocytes from rheumatoid arthritis patients (RA synoviocytes) and signalling pathways involved. PBMCs were pre-treated with IL-6 and soluble IL-6 Receptor (sIL-6R). SFMCs and RA synoviocytes were pre-treated with IL-6/sIL-6R or sIL-6R, alone or in combination with Tocilizumab (TCZ). Cells were stimulated with LPS, S100A8-9, poly(I-C), CpG, Pam2CSK4, MDP, IL-1β. Treatment of PBMCs with IL-6 induced production of TNF-α, CXCL8, and CCL2, but not IL-1β. Addition of IL-6 to the same cells after stimulation with poly(I-C), CpG, Pam2CSK4, and MDP induced a significant increase in IL-1β and CXCL8, but not TNF-α production compared with TLR ligands alone. This enhanced production of IL-1β and CXCL8 paralleled increased p65 NF-κB activation. In contrast, addition of IL-6 to PBMCs stimulated with LPS or S100A8-9 (TLR-4 ligands) led to reduction of IL-1β, TNF-α and CXCL8 with reduced p65 NF-κB activation. IL-6/IL-1β co-stimulation increased CXCL8, CCL2 and IL-6 production. Addition of IL-6 to SFMCs stimulated with LPS or S100A8 increased CXCL8, CCL2 and IL-1β production. Treatment of RA synoviocytes with sIL-6R increased IL-6, CXCL8 and CCL2 production, with increased STAT3 and p65 NF-κB phosphorylation. Our results suggest that IL-6 amplifies TLR-induced inflammatory response. This effect may be relevant in the presence of high IL-6 and sIL-6R levels, such as in arthritic joints in the context of stimulation by endogenous TLR ligands.
登录
查看更多内容
影响因子：
--
作者：
Sokolove, Jeremy;Zhao, Xiaoyan;Chandra, Piyanka E.;Robinson, William H.
通讯作者：
Robinson, William H.
影响因子：
27.4
作者：
Holzinger, Dirk;Frosch, Michael;Wittkowski, Helmut
通讯作者：
Wittkowski, Helmut
影响因子：
158.5
作者：
De Benedetti, Fabrizio;Brunner, Hermine I.;Martini, Alberto
通讯作者：
Martini, Alberto
影响因子：
--
作者：
Samson, Maxime;Audia, Sylvain;Bonnotte, Bernard
通讯作者：
Bonnotte, Bernard
影响因子：
158.5
作者：
Ruperto, Nicolino;Brunner, Hermine I.;Lovell, Daniel J.
通讯作者：
Lovell, Daniel J.