PMID- 34464722 OWN - NLM STAT- MEDLINE DCOM- 20211216 LR - 20211216 IS - 1878-5875 (Electronic) IS - 1357-2725 (Linking) VI - 139 DP - 2021 Oct TI - Estrogen receptor beta alleviates inflammatory lesions in a rat model of inflammatory bowel disease via down-regulating P2X7R expression in macrophages. PG - 106068 LID - S1357-2725(21)00148-5 [pii] LID - 10.1016/j.biocel.2021.106068 [doi] AB - Estrogen receptor beta (ERbeta) agonists could inhibit inflammation in animal models of inflammatory bowel disease (IBD). However, the mechanism underlying such effect and the potential role of P2 x 7 receptor (P2X7R) remains unclear. In the present study, we examined whether the effect of ERbeta activation in IBD rats was related to P2X7R. Overexpression of ERbeta using a recombinant lentivirus in IBD rats improved the IBD-like symptoms, including weight loss, disease activity index (DAI) scores, and inflammatory responses. ERbeta agonists DPN and ERB-041 attenuated P2X7R expression in macrophages from colitis rats and in a murine macrophage cell line (RAW264.7) in response to either lipopolysaccharide (LPS) or adenosine triphosphate (ATP). DPN and ERB-041 also blocked increased production of TNF-alpha, IL-6, and IL-1beta in the rectocolon of colitis rats. The two ERbeta agonists reversed LPS- and ATP-induced up-regulation of P2X7R and its downstream proteins, including NLRP3, ASC, caspase-1, and pro-IL-1beta, in RAW264.7 cells. Also, in both the rectocolon of colitis rats and RAW264.7 cells, ERbeta agonists reversed the up-regulation of extracellular regulated protein kinases (ERK), the Janus kinase 2 (JAK2), and signal transducer and activator of transcription 3 (STAT3), but not up-regulation of serine threonine kinase or cAMP-response element binding protein (CREB). Blockade of JAK2 or STAT3 phosphorylation significantly reduced the ability of DPN to down-regulate P2X7R expression and the ability of ERB-041 and DPN to inhibit IL-1beta release from RAW264.7 cells. We found that ERbeta and P2X7R co-localized in the macrophages of rat rectocolon and in RAW264.7 cells. Deletion of macrophages from colitis rats with clodronate abolished the inhibitory effect of DPN. These results suggest that ERbeta plays an important anti-inflammatory role in IBD rats by down-regulating P2X7R expression and inhibiting IL-1beta release from macrophages through the JAK2/STAT3 signaling pathway. CI - Copyright (c) 2021. Published by Elsevier Ltd. FAU - Jiang, Qian AU - Jiang Q AD - Department of Physiology, Second Military Medical University, Shanghai, 200433, People's Republic of China. Electronic address: jq880117@126.com. FAU - Li, Wenxin AU - Li W AD - Department of Physiology, Second Military Medical University, Shanghai, 200433, People's Republic of China. Electronic address: 995226387@qq.com. FAU - Zhu, Xu AU - Zhu X AD - Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Division of Spine Surgery, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200065, People's Republic of China. Electronic address: zhuxu1632093@163.com. FAU - Yu, Lihua AU - Yu L AD - Department of Physiology, Second Military Medical University, Shanghai, 200433, People's Republic of China. FAU - Lu, Zhanying AU - Lu Z AD - Department of Physiology, Second Military Medical University, Shanghai, 200433, People's Republic of China. FAU - Liu, Yuchen AU - Liu Y AD - Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Division of Spine Surgery, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200065, People's Republic of China. FAU - Ma, Bei AU - Ma B AD - Department of Physiology, Second Military Medical University, Shanghai, 200433, People's Republic of China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Division of Spine Surgery, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200065, People's Republic of China. Electronic address: mabei08@163.com. FAU - Cheng, Liming AU - Cheng L AD - Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Division of Spine Surgery, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200065, People's Republic of China. Electronic address: chlm.d@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210828 PL - Netherlands TA - Int J Biochem Cell Biol JT - The international journal of biochemistry & cell biology JID - 9508482 RN - 0 (Estrogen Receptor beta) SB - IM MH - Animals MH - Colitis MH - *Estrogen Receptor beta MH - Macrophages MH - Mice MH - RAW 264.7 Cells MH - Rats OTO - NOTNLM OT - 2,4,6-trinitrobenzenesulfonic acid (TNBS) OT - Estrogen receptor beta OT - P2X7 receptor OT - inflammatory bowel disease EDAT- 2021/09/01 06:00 MHDA- 2021/12/17 06:00 CRDT- 2021/08/31 20:13 PHST- 2021/01/18 00:00 [received] PHST- 2021/07/25 00:00 [revised] PHST- 2021/08/19 00:00 [accepted] PHST- 2021/09/01 06:00 [pubmed] PHST- 2021/12/17 06:00 [medline] PHST- 2021/08/31 20:13 [entrez] AID - S1357-2725(21)00148-5 [pii] AID - 10.1016/j.biocel.2021.106068 [doi] PST - ppublish SO - Int J Biochem Cell Biol. 2021 Oct;139:106068. doi: 10.1016/j.biocel.2021.106068. Epub 2021 Aug 28.