Human macrophages and monocyte-derived dendritic cells stimulate the proliferation of endothelial cells through midkine production

Abstract

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.

Differential Production of Midkine and Pleiotrophin by Innate APCs upon Stimulation through Nucleic Acid-Sensing TLRs

“…The regulation of both cytokines is also different [ 1 ]. We and others have shown that NF- κ B can regulate MK production, including the production upon TLR triggering in innate APCs [ 24 ]. However, transcription factors like AP1 can regulate the production of PTN [ 4 ].…”

“…MK and PTN play an important role in angiogenesis [ 1 , 15 , 24 , 30 ]. It is interesting to investigate how the innate APCs can modulate angiogenesis and the proliferation of endothelial cells through the differential production of MK and PTN under the different inflammatory conditions, especially under the conditions of tumors and tissue damage where the NAS TLRs have a major role in detecting the damage associated molecular patterns resulting for the injured cells [ 47 ].…”

“…Moreover, MK and PTN were shown to be expressed by some types of immune cells. While MK was shown to be produced by T- and B cells, neutrophils, and mast cells [ 14 , 23 , 24 ], PTN production by these cells was not documented. In contrast, PTN was shown to be produced by some NK subtypes [ 25 ].…”

“…Moreover, MK production was detected in human monocytes and neutrophils [ 26 ], and its production by human macrophage-like cells differentiated from human monocytic cell line (THP-1) cells is debatable [ 27 , 28 ]. We have recently demonstrated that MK is produced by human macrophages, monocyte-derived dendritic cells (MDDCs), and plasmacytoid dendritic cells (pDCs) upon stimulation through TLR4 [ 24 ]. In contrast, PTN production in human monocytes was not previously reported, and THP-1 does not have the capacity to produce PTN [ 29 ], although such production was detected in monocytic cells in quail [ 30 ].…”

“…The production of MK and PTN by innate antigen-presenting cells (iAPCs) is an interesting aspect that requires further investigation. This is due to the fact that monocytes, macrophages, and DCs are implicated in many important physiological mechanisms, including tissue repair and angiogenesis [ 24 , 31 , 32 ], and that MK and PTN are also implicated in these processes [ 24 , 33 ]. Interestingly, Toll-like receptors (TLRs) play an important role in tissue repair, angiogenesis, and immune responses against tumors and infections [ 34 ], especially TLRs 3, 7, 8, and 9, which can detect nucleic acids released from damaged and infected cells [ 35 , 36 ].…”