PMID- 37326695 OWN - NLM STAT- MEDLINE DCOM- 20230719 LR - 20230719 IS - 1420-908X (Electronic) IS - 1023-3830 (Linking) VI - 72 IP - 7 DP - 2023 Jul TI - Loss of TRIM24 promotes IL-10 expression via CBP/p300-dependent IFNbeta1 transcription during macrophage activation. PG - 1441-1452 LID - 10.1007/s00011-023-01751-x [doi] AB - BACKGROUND: As an anti-inflammatory cytokine, interleukin 10 (IL-10) plays a vital role in preventing inflammatory and autoimmune pathologies while also maintaining immune homeostasis. IL-10 production in macrophages is tightly regulated by multiple pathways. TRIM24, a member of the Transcriptional Intermediary Factor 1 (TIF1) family, contributes to antiviral immunity and macrophage M2 polarization. However, the role of TRIM24 in regulating IL-10 expression and its involvement in endotoxic shock remains unclear. METHODS: In vitro, bone marrow derived macrophages cultured with GM-CSF or M-CSF were stimulated with LPS (100ng/ml). Murine models of endotoxic shock were established by challenging the mice with different dose of LPS (i.p). RTPCR, RNA sequencing, ELISA and hematoxylin and eosin staining were performed to elucidate the role and mechanisms of TRIM24 in endotoxic shock. RESULTS: The expression of TRIM24 is downregulated in LPS-stimulated bone marrow-derived macrophages (BMDMs). Loss of TRIM24 boosted IL-10 expression during the late stage of LPS-stimulation in macrophages. RNA-seq analysis revealed the upregulation of IFNbeta1, an upstream regulator of IL-10, in TRIM24 knockout macrophages. Treatment with C646, a CBP/p300 inhibitor, diminished the difference in both IFNbeta1 and IL-10 expression between TRIM24 knockout and control macrophages. Loss of TRIM24 provided protection against LPS-induced endotoxic shock in mice. CONCLUSION: Our results demonstrated that inhibiting TRIM24 promoted the expression of IFNbeta1 and IL-10 during macrophage activation, therefore protecting mice from endotoxic shock. This study offers novel insights into the regulatory role of TRIM24 in IL-10 expression, making it a potentially attractive therapeutic target for inflammatory diseases. CI - (c) 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG. FAU - Hui, Zhaoyuan AU - Hui Z AUID- ORCID: 0000-0003-0436-8550 AD - Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China. AD - Department of Pathogenic Biology and Medical Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. AD - Department of Genetics, Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, 310058, China. AD - Ningxia Key Laboratory of Prevention and Control of Common Infectious Diseases, Yinchuan, 750004, China. FAU - Fu, Yuanzheng AU - Fu Y AD - Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China. AD - Department of Genetics, Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, 310058, China. FAU - Chen, Yunyun AU - Chen Y AD - Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China. AD - Department of Genetics, Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, 310058, China. FAU - Yin, Jie AU - Yin J AD - Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China. AD - Department of Genetics, Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, 310058, China. FAU - Fang, Hui AU - Fang H AD - Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China. AD - Department of Genetics, Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, 310058, China. FAU - Tu, Yifan AU - Tu Y AD - Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China. AD - Department of Genetics, Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, 310058, China. FAU - Gu, Ying AU - Gu Y AD - Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China. guyinghz@zju.edu.cn. AD - Department of Genetics, Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, 310058, China. guyinghz@zju.edu.cn. AD - Zhejiang Provincial Key Lab of Genetic and Developmental Disorder, Hangzhou, 310058, Zhejiang, China. guyinghz@zju.edu.cn. AD - Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, 311121, China. guyinghz@zju.edu.cn. FAU - Zhang, Jiawei AU - Zhang J AD - Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China. jwzhang@zju.edu.cn. LA - eng GR - 31900638/National Natural Science Foundation of China/ GR - 31970555/National Natural Science Foundation of China/ GR - 32100477/National Natural Science Foundation of China/ GR - 32070630/National Natural Science Foundation of China/ GR - XT2022006/The University-level scientific research project of Ningxia Medical University/ GR - 2018YFA0800102/National Key R&D Project of China/ GR - 2020R01006/Zhejiang Innovation Team Grant/ PT - Journal Article DEP - 20230616 PL - Switzerland TA - Inflamm Res JT - Inflammation research : official journal of the European Histamine Research Society ... [et al.] JID - 9508160 RN - 130068-27-8 (Interleukin-10) RN - 0 (Lipopolysaccharides) RN - 0 (Cytokines) SB - IM MH - Mice MH - Animals MH - *Interleukin-10/genetics/metabolism MH - Lipopolysaccharides/pharmacology/metabolism MH - Macrophage Activation MH - Macrophages MH - Cytokines/metabolism MH - *Shock, Septic/metabolism OTO - NOTNLM OT - CBP/p300 OT - IFNbeta1 OT - IL-10 OT - TRIM24 EDAT- 2023/06/16 13:10 MHDA- 2023/07/19 06:42 CRDT- 2023/06/16 11:08 PHST- 2022/01/20 00:00 [received] PHST- 2023/05/03 00:00 [accepted] PHST- 2023/03/25 00:00 [revised] PHST- 2023/07/19 06:42 [medline] PHST- 2023/06/16 13:10 [pubmed] PHST- 2023/06/16 11:08 [entrez] AID - 10.1007/s00011-023-01751-x [pii] AID - 10.1007/s00011-023-01751-x [doi] PST - ppublish SO - Inflamm Res. 2023 Jul;72(7):1441-1452. doi: 10.1007/s00011-023-01751-x. Epub 2023 Jun 16.