Th17 cells favor inflammatory responses while inhibiting type I collagen deposition by dermal fibroblasts: differential effects in healthy and systemic sclerosis fibroblasts.
Th17 cells favor inflammatory responses while inhibiting type I collagen deposition by dermal fibroblasts: differential effects in healthy and systemic sclerosis fibroblasts.
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DOI：
10.1186/ar4334
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发表时间：
2013-10-10
影响因子：
4.9
通讯作者：
Chizzolini C
中科院分区：
文献类型：
--
作者：
Brembilla NC;Montanari E;Truchetet ME;Raschi E;Meroni P;Chizzolini C
系统性硬化症（SSc）中辅助性T细胞（Th）-17细胞增加。因此，我们评估了Th 17细胞是否可以调节来自健康供体（HD）和SSc个体的真皮成纤维细胞中的炎症和纤维化反应。从14个SSc和8个HD皮肤活检中获得成纤维细胞。在富集CC趋化因子受体（CCR）-4/CCR6/CD 161表达细胞后，从健康外周血产生Th 17克隆。通过流式细胞术和多重珠免疫测定来评估它们的细胞因子产生。通过酶联免疫吸附试验（ELISA）和放射免疫测定（RIA）定量测定成纤维细胞产生的单核细胞趋化蛋白（MCP）-1、白细胞介素（IL）-8、基质金属蛋白酶（MMP）-1、金属蛋白酶组织抑制剂（TIMP）-1、MMP-2和I型胶原，并通过实时PCR评估其转录水平的变化。通过蛋白质印迹和使用药理学抑制剂分析细胞内信号。使用IL-17 A、肿瘤坏死因子（TNF）和干扰素-γ（IFN-γ）阻断试剂评估观察到的效应的特异性。IL-17 A以剂量依赖性方式增加MCP-1、IL-8和MMP-1的产生，而在蛋白质和mRNA水平上对HD和SSc成纤维细胞中的I型胶原没有影响。核因子-κ B（NF-κB）和p38优先参与MCP-1和IL-8的诱导，而MMP-1最依赖于c-Jun N-末端激酶（JNK）。活化的Th 17克隆的上清液大大增强MCP-1、IL-8和MMP-1，同时强烈抑制胶原蛋白的产生。值得注意的是，与HD成纤维细胞相比，SSc中MCP-1和IL-8的产生更高，而胶原抑制更低。Th 17克隆上清液效应主要依赖于IL-17 A、TNF和部分IFN-γ之间的相加/协同活性。重要的是，由Th 17克隆上清液诱导的I型胶原蛋白产生的抑制通过主要在SSc成纤维细胞中的IL-17 A、TNF和IFN-γ的阻断而完全消除，揭示了对SSc中抑制信号的内在抗性。我们的研究结果表明，在体外Th 17细胞引起促炎反应，同时抑制胶原蛋白的产生。因此，在SSc中观察到的Th 17细胞数量增加可能影响疾病的炎症组分，同时潜在地提供针对纤维化的保护作用。
T helper (Th)-17 cells are increased in systemic sclerosis (SSc). We therefore assessed whether Th17 cells could modulate the inflammatory and fibrotic responses in dermal fibroblasts from healthy donors (HD) and SSc individuals. Fibroblasts were obtained from 14 SSc and 8 HD skin biopsies. Th17 clones were generated from healthy peripheral blood upon enrichment of CC chemokine receptor (CCR)-4/CCR6/CD161 expressing cells. Their cytokine production was assessed by flow cytometry and multiplex beads immunoassay. Fibroblast production of monocyte chemoattractant protein (MCP)-1, interleukin (IL)-8, matrix metalloproteinase (MMP)-1, tissue inhibitor of metalloproteinase (TIMP)-1, MMP-2 and type-I collagen was quantified by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), and changes in their transcription levels assessed by real-time PCR. Intracellular signals were dissected by western blot and the use of pharmacological inhibitors. IL-17A, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) blocking reagents were used to assess the specificity of the observed effects. IL-17A increased MCP-1, IL-8 and MMP-1 production in a dose-dependent manner while having no effect on type I collagen in HD and SSc fibroblasts both at protein and mRNA levels. Nuclear factor-kappa B (NF-κB) and p38 were preferentially involved in the induction of MCP-1 and IL-8, while MMP-1 was most dependent on c-Jun N-terminal kinase (JNK). Supernatants of activated Th17 clones largely enhanced MCP-1, IL-8 and MMP-1 while strongly inhibiting collagen production. Of note, the production of MCP-1 and IL-8 was higher, while collagen inhibition was lower in SSc compared to HD fibroblasts. The Th17 clone supernatant effects were mostly dependent on additive/synergistic activities between IL-17A, TNF and in part IFN-γ. Importantly, the inhibition of type I collagen production induced by the Th17 clone supernatants was completely abrogated by blockade of IL-17A, TNF and IFN-γ mostly in SSc fibroblasts, revealing an intrinsic resistance to inhibitory signals in SSc. Our findings demonstrate that in vitro Th17 cells elicit pro-inflammatory responses while restraining collagen production. Thus, the increased Th17 cell number observed in SSc may impact on the inflammatory component of the disease simultaneously potentially providing a protective role against fibrosis.
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DOI：
10.1152/ajpheart.00928.2007
发表时间：
2007-12-01
影响因子：
4.8
作者：
Cortez, Dolores M.;Feldman, Marc D.;Chandrasekar, Bysani
通讯作者：
Chandrasekar, Bysani
影响因子：
4.9
作者：
Hwang SY;Kim JY;Kim KW;Park MK;Moon Y;Kim WU;Kim HY
通讯作者：
Kim HY
人白细胞介素17产生的细胞起源于CD161+ CD4+ T细胞前体。
影响因子：
15.3
作者：
Cosmi, Lorenzo;De Palma, Raffaele;Santarlasci, Veronica;Maggi, Laura;Capone, Manuela;Frosali, Francesca;Rodolico, Gabriella;Querci, Valentina;Abbate, Gianfranco;Angeli, Roberta;Berrino, Liberato;Fambrini, Massimiliano;Caproni, Marzia;Tonelli, Francesco;Lazzeri, Elena;Parronchi, Paola;Liotta, Francesco;Maggi, Enrico;Romagnani, Sergio;Annunziato, Francesco
通讯作者：
Annunziato, Francesco
影响因子：
20.3
作者：
Chizzolini, Carlo;Chicheportiche, Rachel;Dayer, Jean-Michel
通讯作者：
Dayer, Jean-Michel
影响因子：
30.5
作者：
Duhen, Thomas;Geiger, Rebekka;Sallusto, Federica
通讯作者：
Sallusto, Federica