TNF-anti-TNF Immune Complexes Inhibit IL-12/IL-23 Secretion by Inflammatory Macrophages via an Fc-dependent Mechanism
TNF-anti-TNF Immune Complexes Inhibit IL-12/IL-23 Secretion by Inflammatory Macrophages via an Fc-dependent Mechanism
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DOI：
10.1093/ecco-jcc/jjy075
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发表时间：
2018-09-01
影响因子：
8
通讯作者：
Wildenberg, Manon E.
中科院分区：
文献类型：
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作者：
Bloemendaal, Felicia M.;Koelink, Pim J.;Wildenberg, Manon E.
背景和目标：我们最近发现，IgG 1抗肿瘤坏死因子[TNF]抗体在炎症性肠病[IBD]中的作用模式需要巨噬细胞上的Fc γ受体[Fc γ R]参与。在这里，我们研究的影响Fc γ受体信号的抗TNF对巨噬细胞IL-12/IL-23的secretory.Methods：细胞因子的生产由人类炎症巨噬细胞在RNA和蛋白质的水平进行了评估。TNF-抗TNF免疫复合物的形成通过尺寸排阻色谱法测定，并通过免疫荧光观察信号传导。结果：英夫利昔单抗和阿达木单抗能有效地抑制炎症巨噬细胞产生IL-12/IL-23，而Fab'片段赛妥珠单抗则不能。IL-12/IL-23抑制依赖于Syk活性，并在IL-12/IL-23 p40 mRNA水平介导。依那西普是一种与Fc区融合的可溶性TNF受体，不抑制IL-12/L-23分泌，表明Fc区的存在是不够的。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，这表明Fc γ R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IgG 1免疫复合物，而不是未复合的IgG 1，类似地抑制IL-12/IL-23分泌。最后，英夫利西单抗显着降低IL-12/IL-23 p40生产的髓系细胞分离固有层的IBD patients.Conclusions：TNF-抗-TNF抗体免疫复合物强效抑制IL-12/IL-23表达的炎症巨噬细胞。我们的数据表明，抗肿瘤坏死因子和抗体对IL-12/IL-23因此可能有部分重叠的作用模式与IBD患者。
Background and Aims: We have recently shown that the mode of action of IgG1 anti-tumour necrosis factor [TNF] antibodies in inflammatory bowel disease [IBD] requires Fc gamma-receptor [Fc gamma R] engagement on macrophages. Here we examine the effect of Fc gamma-receptor signalling by anti-TNF on macrophage IL-12/IL-23 secretion.Methods: 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.Results: 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 Fc gamma R-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.Conclusions: 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.