Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
J Crohns Colitis. 2018 Aug 29;12(9):1122-1130. doi: 10.1093/ecco-jcc/jjy075.
We have recently shown that the mode of action of IgG1 anti-tumour necrosis factor [TNF] antibodies in inflammatory bowel disease [IBD] requires Fcγ-receptor [FcγR] engagement on macrophages. Here we examine the effect of Fcγ-receptor signalling by anti-TNF on macrophage IL-12/IL-23 secretion.
Cytokine production by human inflammatory macrophages was assessed at the level of RNA and protein. TNF-anti-TNF immune complex formation was determined by size-exclusion chromatography and signalling visualized by immunofluorescence. IL-12/IL-23p40 was measured in CD14+ lamina propria cells from IBD patients.
Infliximab and adalimumab potently suppressed IL-12/IL-23 production by inflammatory macrophages, but Fab' fragment certolizumab did not. IL-12/IL-23 suppression depended on Syk activity and was mediated at the level of IL-12/IL-23p40 mRNA. Etanercept, a soluble TNF receptor fused to an Fc-region, did not inhibit IL-12/L-23 secretion, suggesting that the presence of an Fc-region was not sufficient. Infliximab and adalimumab formed immune complexes with soluble TNF whereas etanercept did not, suggesting that FcγR-mediated suppression of IL-12/IL-23 required the formation of immune complexes. Indeed, non-specific IgG1 immune complexes, but not uncomplexed IgG1, similarly suppressed IL-12/IL-23 secretion. Finally, infliximab significantly decreased IL-12/IL-23p40 production in myeloid cells isolated from the lamina propria of IBD patients.
TNF-anti-TNF antibody immune complexes potently inhibit IL-12/IL-23 expression by inflammatory macrophages. Our data suggest that anti-TNFs and antibodies against IL-12/IL-23 may therefore have partially overlapping modes of action in patients with IBD.
我们最近发现，在炎症性肠病（IBD）中，IgG1 抗肿瘤坏死因子（TNF）抗体的作用模式需要巨噬细胞上 Fcγ 受体（FcγR）的参与。在这里，我们研究了抗 TNF 对巨噬细胞 IL-12/IL-23 分泌的 FcγR 信号转导的影响。
通过细胞因子产生水平的 RNA 和蛋白质评估人炎症性巨噬细胞的细胞因子产生。通过排阻层析法测定 TNF-抗 TNF 免疫复合物的形成，并通过免疫荧光可视化信号转导。从 IBD 患者的 CD14+ 固有层细胞中测量 IL-12/IL-23p40。
英夫利昔单抗和阿达木单抗强烈抑制炎症性巨噬细胞产生 IL-12/IL-23，但 Fab' 片段 Certolizumab 则没有。IL-12/IL-23 抑制依赖于 Syk 活性，并在 IL-12/IL-23p40 mRNA 水平上进行介导。可溶性 TNF 受体与 Fc 区融合的依那西普不抑制 IL-12/L-23 分泌，表明存在 Fc 区还不够。英夫利昔单抗和阿达木单抗与可溶性 TNF 形成免疫复合物，而依那西普则没有，表明 FcγR 介导的 IL-12/IL-23 抑制需要形成免疫复合物。事实上，非特异性 IgG1 免疫复合物，而不是未结合的 IgG1，同样抑制 IL-12/IL-23 分泌。最后，英夫利昔单抗显著降低了从 IBD 患者固有层分离的髓样细胞中 IL-12/IL-23p40 的产生。
TNF-抗 TNF 抗体免疫复合物强烈抑制炎症性巨噬细胞中 IL-12/IL-23 的表达。我们的数据表明，抗 TNFs 和抗 IL-12/IL-23 抗体在 IBD 患者中可能具有部分重叠的作用模式。
