Department of Microbiology and Immunology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
PLoS One. 2022 Apr 27;17(4):e0267662. doi: 10.1371/journal.pone.0267662. eCollection 2022.
The cytokine midkine (MK) is a growth factor that is involved in different physiological processes including tissue repair, inflammation, the development of different types of cancer and the proliferation of endothelial cells. The production of MK by primary human macrophages and monocyte-derived dendritic cells (MDDCs) was never described. We investigated whether MK is produced by primary human monocytes, macrophages and MDDCs and the capacity of macrophages and MDDCs to modulate the proliferation of endothelial cells through MK production. The TLR stimulation of human monocytes, macrophages and MDDCs induced an average of ≈200-fold increase in MK mRNA and the production of an average of 78.2, 62, 179 pg/ml MK by monocytes, macrophages and MDDCs respectively (p < 0.05). MK production was supported by its detection in CD11c+ cells, CLEC4C+ cells and CD68+ cells in biopsies of human tonsils showing reactive lymphoid follicular hyperplasia. JSH-23, which selectively inhibits NF-κB activity, decreased the TLR-induced production of MK in PMBCs, macrophages and MDDCs compared to the control (p < 0.05). The inhibition of MK production by macrophages and MDDCs using anti-MK siRNA decreased the capacity of their supernatants to stimulate the proliferation of endothelial cells (p = 0.01 and 0.04 respectively). This is the first study demonstrating that the cytokine MK is produced by primary human macrophages and MDDCs upon TLR triggering, and that these cells can stimulate endothelial cell proliferation through MK production. Our results also suggest that NF-κB plays a potential role in the production of MK in macrophages and MDDCs upon TLR stimulation. The production of MK by macrophages and MDDCs and the fact that these cells can enhance the proliferation of endothelial cells by producing MK are novel immunological phenomena that have potentially important therapeutic implications.
细胞因子中期因子 (MK) 是一种生长因子，参与包括组织修复、炎症、不同类型癌症的发展和内皮细胞增殖在内的不同生理过程。原代人巨噬细胞和单核细胞衍生的树突状细胞 (MDDC) 产生 MK 的情况从未被描述过。我们研究了 MK 是否由原代人单核细胞、巨噬细胞和 MDDC 产生，以及巨噬细胞和 MDDC 通过 MK 产生来调节内皮细胞增殖的能力。TLR 刺激人单核细胞、巨噬细胞和 MDDC 诱导 MK mRNA 平均增加约 200 倍，单核细胞、巨噬细胞和 MDDC 分别产生平均 78.2、62、179 pg/ml 的 MK(p<0.05)。MK 的产生得到了支持，因为在人扁桃体活检中，CD11c+细胞、CLEC4C+细胞和 CD68+细胞中检测到了 MK。JSH-23 选择性抑制 NF-κB 活性，与对照相比，减少了 PMBCs、巨噬细胞和 MDDC 中 TLR 诱导的 MK 产生(p<0.05)。巨噬细胞和 MDDC 用抗 MK siRNA 抑制 MK 产生，降低了其上清液刺激内皮细胞增殖的能力(p=0.01 和 0.04)。这是第一项研究表明，细胞因子 MK 是由原代人巨噬细胞和 MDDC 在 TLR 触发时产生的，并且这些细胞可以通过产生 MK 刺激内皮细胞增殖。我们的结果还表明，NF-κB 在 TLR 刺激后巨噬细胞和 MDDC 中 MK 的产生中可能发挥作用。巨噬细胞和 MDDC 产生 MK，以及这些细胞可以通过产生 MK 增强内皮细胞增殖的事实，是潜在具有重要治疗意义的新的免疫学现象。
