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Differential Production of Midkine and Pleiotrophin by Innate APCs upon Stimulation through Nucleic Acid-Sensing TLRs
Elias A Said1, Sumaya Al-Dughaishi1, Wadha Al-Hatmi1
1Department of Microbiology and Immunology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
Abstract:
Midkine (MK) and pleiotrophin (PTN) belong to the same family of cytokines. They have similar sequences and functions. Both have important roles in cellular proliferation, tumors, and diseases. They regulate and are expressed by some immune cells. We have recently demonstrated MK production by some human innate antigen-presenting cells (iAPCs), i.e., monocyte-derived dendritic cells (MDDCs) and macrophages stimulated through Toll-like receptor (TLR)-4, and plasmacytoid dendritic cells (pDCs) stimulated through TLR 7. While PTN production was only documented in tissue macrophages. TLRs 3, 7, 8, and 9 are nucleic acid sensing (NAS) TLRs that detect nucleic acids from cell damage and infection and induce iAPC responses. We investigated whether NAS TLRs can induce MK and PTN production by human iAPCs, namely monocytes, macrophages, MDDCs, myeloid dendritic cells (mDCs), and pDCs. Our results demonstrated for the first time that PTN is produced by all iAPCs upon TLR triggering (p < 0.01). IAPCs produced more PTN than MK (p < 0.01). NAS TLRs and iAPCs had differential abilities to induce the production of MK, which was induced in monocytes and pDCs by all NAS TLRs (p < 0.05) and in MDDCs by TLRs 7/8 (p < 0.05). TLR4 induced a stronger MK production than NAS TLRs (p ≤ 0.05). Monocytes produced higher levels of PTN after differentiation to macrophages and MDDCs (p < 0.05). The production of MK and PTN differs among iAPCs, with a higher production of PTN and a selective induction of MK production by NAS TLR. This highlights the potentially important role of iAPCs in angiogenesis, tumors, infections, and autoimmunity through the differential production of MK and PTN upon TLR triggering.
Insights
Midkine (MK) and pleiotrophin (PTN) are cytokines involved in cell growth and disease. This study shows that nucleic acid-sensing Toll-like receptors (TLRs) induce PTN production by all innate antigen-presenting cells (iAPCs) and selectively induce MK production.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Midkine (MK) and pleiotrophin (PTN) are related cytokines crucial for cellular processes, including proliferation, and are implicated in various diseases.
- Previous research indicated MK production by specific innate antigen-presenting cells (iAPCs) like monocyte-derived dendritic cells (MDDCs) and macrophages stimulated via Toll-like receptor (TLR)-4, and plasmacytoid dendritic cells (pDCs) via TLR 7.
- Pleiotrophin (PTN) production was previously documented only in tissue macrophages.
Purpose of the Study:
- To investigate the induction of Midkine (MK) and Pleiotrophin (PTN) production by human iAPCs, including monocytes, macrophages, MDDCs, myeloid dendritic cells (mDCs), and pDCs, upon stimulation with nucleic acid-sensing Toll-like receptors (NAS TLRs).
- To compare the production levels of MK and PTN induced by NAS TLRs and TLR4 across different iAPC subsets.
Main Methods:
- Human iAPCs (monocytes, macrophages, MDDCs, mDCs, pDCs) were stimulated with various Toll-like receptors (TLRs), including NAS TLRs (3, 7, 8, 9) and TLR4.
- Production of MK and PTN by iAPCs was quantified following TLR stimulation.
Main Results:
- For the first time, PTN production was demonstrated in all investigated iAPCs upon TLR triggering, with higher levels than MK (p < 0.01).
- NAS TLRs differentially induced MK production across iAPCs: monocytes and pDCs responded to all NAS TLRs (p < 0.05), while MDDCs were induced by TLRs 7/8 (p < 0.05).
- TLR4 induced significantly stronger MK production than NAS TLRs (p ≤ 0.05). Monocyte differentiation into macrophages and MDDCs enhanced PTN production (p < 0.05).
Conclusions:
- Innate antigen-presenting cells (iAPCs) exhibit differential production of MK and PTN in response to TLR stimulation, with PTN being more broadly produced.
- Nucleic acid-sensing TLRs selectively induce MK production in specific iAPCs, while TLR4 is a potent inducer of MK.
- These findings highlight the significant role of iAPCs in regulating processes like angiogenesis, tumor development, infections, and autoimmunity through the differential expression of MK and PTN.
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