小剂量肿瘤坏死因子受体生物制剂抑制肿瘤坏死因子-p38 信号通路和炎症。

Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation.

机构信息

Department of Immunopathology, SA Pathology, Women's and Children's Hospital, North Adelaide, SA, 5006, Australia.

Discipline of Paediatrics, School of Medicine, Robinson Research Institute, University of Adelaide, Adelaide, SA, 5001, Australia.

出版信息

Nat Commun. 2018 Apr 10;9(1):1365. doi: 10.1038/s41467-018-03640-y.

Despite anti-TNF therapy advancements for inflammatory diseases such as rheumatoid arthritis, the burden of diseases remains high. An 11-mer TNF peptide, TNF, is known to stimulate selective functional responses compared to the parent TNF molecule. Here, we show that TNF binds to the TNF receptor, activating p38 MAP kinase through TNF receptor-associated factor 2. Using truncated TNFR mutants, we identify the sequence in TNFRI which enables p38 activation by TNF. Peptides with this TNFRI sequence, such as TNFRI bind to TNF and inhibit TNF-induced p38 activation, respiratory burst, cytokine production and adhesion receptor expression but not F-Met-Leu-Phe-induced respiratory burst in neutrophils. TNFRI does not prevent TNF binding to TNFRI or TNF-induced stimulation of ERK, JNK and NF-κB. TNFRI inhibits bacterial lipopolysaccharide-induced peritonitis, carrageenan-induced and antigen-induced paw inflammation, and respiratory syncytial virus-induced lung inflammation in mice. Our findings suggest a way of targeting TNF-p38 pathway to treat chronic inflammatory disorders.

尽管抗 TNF 疗法在治疗类风湿性关节炎等炎症性疾病方面取得了进展，但疾病负担仍然很高。一种 11 肽 TNF 与母体 TNF 分子相比，已知能刺激选择性的功能反应。在这里，我们发现 TNF 与 TNF 受体结合，通过 TNF 受体相关因子 2 激活 p38 MAP 激酶。使用截断的 TNFR 突变体，我们确定了 TNFRI 中的序列，该序列使 TNF 能够激活 p38。具有这种 TNFRI 序列的肽，如 TNFRI 与 TNF 结合并抑制 TNF 诱导的 p38 激活、呼吸爆发、细胞因子产生和粘附受体表达，但不能抑制中性粒细胞中 F-Met-Leu-Phe 诱导的呼吸爆发。TNFRI 不会阻止 TNF 与 TNFRI 结合或 TNF 诱导的 ERK、JNK 和 NF-κB 刺激。TNFRI 抑制细菌脂多糖诱导的腹膜炎、角叉菜胶诱导的和抗原诱导的爪炎症以及呼吸道合胞病毒诱导的小鼠肺炎症。我们的研究结果表明了一种靶向 TNF-p38 途径治疗慢性炎症性疾病的方法。