Blockade of IL-6 Trans signaling attenuates pulmonary fibrosis.
Blockade of IL-6 Trans signaling attenuates pulmonary fibrosis.
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DOI：
10.4049/jimmunol.1302470
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发表时间：
2014-10-01
期刊：
影响因子：
--
通讯作者：
Blackburn MR
中科院分区：
文献类型：
--
作者：
Le TT;Karmouty-Quintana H;Melicoff E;Le TT;Weng T;Chen NY;Pedroza M;Zhou Y;Davies J;Philip K;Molina J;Luo F;George AT;Garcia-Morales LJ;Bunge RR;Bruckner BA;Loebe M;Seethamraju H;Agarwal SK;Blackburn MR
特发性肺纤维化（IPF）是一种致命的肺部疾病，具有进行性纤维化，并在诊断后2-3年内死亡。IPF的发病率和患病率每年都在增加，有效的治疗方法很少。抑制白细胞介素6（IL-6）导致小鼠肺纤维化的减轻。尚不清楚这是由于膜结合IL-6受体α（mIL-6 R α）介导的经典信号传导阻断，还是由于可溶性IL-6 R α（sIL-6 R α）介导的反式信号传导阻断。我们的研究评估了sL-6 R α在IPF中的作用。我们证实了IPF患者和小鼠在纤维化发作和进展期间sIL-6 R α升高。我们证明了蛋白酶介导的肺巨噬细胞裂解在sL-6 R α的产生中是重要的。体内sIL-6 R α中和可减轻小鼠肺纤维化，表现为肺中肌成纤维细胞、纤连蛋白和胶原蛋白减少。体外IL-6反式信号的激活增强了成纤维细胞增殖和细胞外基质蛋白的产生，这些作用与肺纤维化的进展相关。总之，这些发现表明，从患病肺中的巨噬细胞产生的sL-6 R α有助于IL-6反式信号传导，进而影响肺纤维化中的关键事件。
Idiopathic Pulmonary Fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2–3 years of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of interleukin 6 (IL-6) results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6 receptor alpha (mIL-6Rα), or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sL-6Rα. In vivo neutralization of sIL-6Rα attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Together these findings demonstrate that the production of sL-6Rα from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.
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DOI：
10.1046/j.1432-1327.2000.01278.x
发表时间：
2000-05-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Althoff, K;Reddy, P;Müllberg, J
通讯作者：
Müllberg, J
DOI：
10.1046/j.1432-1327.2001.01867.x
发表时间：
2001-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Jostock, T;Müllberg, J;Rose-John, S
通讯作者：
Rose-John, S
影响因子：
5.8
作者：
Booth, Brian W.;Sandifer, Tracy;Martin, Linda D.
通讯作者：
Martin, Linda D.
影响因子：
--
作者：
Franchimont, N;Lambert, C;Malaise, M
通讯作者：
Malaise, M
影响因子：
4.4
作者：
Briso, Eva M.;Dienz, Oliver;Rincon, Mercedes
通讯作者：
Rincon, Mercedes