PMID- 37196867 OWN - NLM STAT- MEDLINE DCOM- 20230619 LR - 20240306 IS - 1878-5492 (Electronic) IS - 0966-3274 (Linking) VI - 79 DP - 2023 Aug TI - Minocycline induces tolerance to dendritic cell production probably by targeting the SOCS1/ TLR4/NF-kappaB signaling pathway. PG - 101856 LID - S0966-3274(23)00073-4 [pii] LID - 10.1016/j.trim.2023.101856 [doi] AB - OBJECTIVE: Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in maintaining peripheral immune tolerance. The use of tolerogenic DCs (tolDCs), i.e., semi-mature DCs that express co-stimulatory molecules but not pro-inflammatory cytokines, has been proposed. However, the mechanism of tolDCs induced by minocycline is still unclear. Our previous bioinformatics analyses based on multiple databases suggested that the suppressor of cytokine signaling 1/Toll-like receptor 4/NF-kappaB (SOCS1/TLR4/NF-kappaB) signal pathway was associated with DCs maturation. Thus, we studied whether minocycline could induce DC tolerance through this pathway. METHODS: A search for potential targets was carried out through public databases, and pathway analysis was performed on these potential targets to obtain pathways relevant to the experiment. Flow cytometry was used to detect the expression of DC surface markers CD11c, CD86, and CD80, and major histocompatibility complex II. The secretion of interleukin (IL)-12p70, tumor necrosis factor alpha (TNF- alpha), and IL-10 in the DC supernatant was detected by enzyme-linked immunoassay. The ability of three groups (Ctrl-DCs, Mino-DCs, and LPS-DCs) of DCs to stimulate allogeneic CD4+ T cells was analyzed using a mixed lymphocyte reaction assay. Western blotting was used to detect the expression of TLR4, NF-kappaB-p65, NF-kappaB-p-p65, IkappaB-alpha, and SOCS1 proteins. RESULTS: The hub gene plays a vital role in biological processes; in related pathways, the regulation of other genes is often affected by it. The SOCS1/TLR4/NF-kappaB signaling pathway was further validated by searching for potential targets through public databases to obtain relevant pathways. The minocycline-induced tolDCs showed characteristics of semi-mature DCs. Moreover, the IL-12p70 and TNF-alpha levels in the minocycline-stimulated DC group (Mino-DC group) were lower than those in the lipopolysaccharide (LPS)-DC group, and the IL-10 levels were higher in the Mino-DC group than in the LPS-DC and control DC groups. In addition, the Mino-DC group had decreased protein expression levels of TLR4 and NF-kappaB-p65 and upregulated protein levels of NF-kappaB-p-p65, IkappaB-alpha, and SOCS1 compared with the other groups. CONCLUSION: The results of this study indicate that minocycline could improve the tolerance of DCs probably by blocking the SOCS1/TLR4/NF-kappaB signaling pathway. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Han, Xu AU - Han X AD - Department of Neurology, Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People's Republic of China. FAU - Wei, Qiao AU - Wei Q AD - Department of Neurology, Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People's Republic of China. FAU - Xu, Rui-Xue AU - Xu RX AD - Department of Neurology, Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People's Republic of China. FAU - Wang, Shi AU - Wang S AD - Department of Neurology, Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People's Republic of China. FAU - Liu, Xue-Yu AU - Liu XY AD - Department of Neurology, Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People's Republic of China. FAU - Guo, Cong AU - Guo C AD - Department of Neurology, Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People's Republic of China. FAU - Gao, Qian AU - Gao Q AD - Department of Neurology, Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People's Republic of China. FAU - Zhou, Xuan AU - Zhou X AD - Department of Neurology, Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People's Republic of China. FAU - Chen, Li-Ping AU - Chen LP AD - Department of Neurology, Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People's Republic of China. Electronic address: chenlp1624@outlook.com. FAU - Li, Zhen-Fei AU - Li ZF AD - Department of Neurology, Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People's Republic of China. LA - eng GR - 81471228/National Natural Science Foundation of China/ GR - NO. 20200048/Hebei Medical Science Research Project/ PT - Journal Article DEP - 20230516 PL - Netherlands TA - Transpl Immunol JT - Transplant immunology JID - 9309923 RN - 0 (NF-kappa B) RN - 130068-27-8 (Interleukin-10) RN - FYY3R43WGO (Minocycline) RN - 139874-52-5 (NF-KappaB Inhibitor alpha) RN - 0 (Lipopolysaccharides) RN - 0 (Toll-Like Receptor 4) RN - 0 (Suppressor of Cytokine Signaling Proteins) RN - 187348-17-0 (Interleukin-12) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - *NF-kappa B/metabolism MH - *Interleukin-10/metabolism MH - Minocycline/pharmacology/metabolism MH - NF-KappaB Inhibitor alpha/metabolism MH - Lipopolysaccharides/pharmacology MH - Toll-Like Receptor 4/metabolism MH - Signal Transduction MH - Suppressor of Cytokine Signaling Proteins/genetics/metabolism MH - Interleukin-12 MH - Tumor Necrosis Factor-alpha/metabolism MH - Immune Tolerance MH - Dendritic Cells OTO - NOTNLM OT - Minocycline OT - NF-kB OT - SOCS1 OT - Tolerogenic dendritic cells COIS- Declaration of Competing Interest The authors declare no conflict of interest. EDAT- 2023/05/18 01:07 MHDA- 2023/06/19 13:09 CRDT- 2023/05/17 19:26 PHST- 2023/01/18 00:00 [received] PHST- 2023/04/10 00:00 [revised] PHST- 2023/05/13 00:00 [accepted] PHST- 2023/06/19 13:09 [medline] PHST- 2023/05/18 01:07 [pubmed] PHST- 2023/05/17 19:26 [entrez] AID - S0966-3274(23)00073-4 [pii] AID - 10.1016/j.trim.2023.101856 [doi] PST - ppublish SO - Transpl Immunol. 2023 Aug;79:101856. doi: 10.1016/j.trim.2023.101856. Epub 2023 May 16.