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Substance P Mediates Estrogen Modulation Proinflammatory Cytokines Release in Intervertebral Disc

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Abstract

Intervertebral disc degeneration (IDD) is a main contributor to low back pain. A close relationship exists between inflammation and pain. Estrogen can affect inflammation and may play a crucial role in IDD and pain. Substance P (SP) can also regulate the expression of pro-inflammatory cytokines in intervertebral disc (IVD). This study aimed to investigate the potential role of SP in estrogen regulation of IDD. Nine-week-old C57BL/6 female mice were divided into four groups as follows: sham surgery (sham), ovariectomy (OVX), ovariectomy plus estrogen replacement therapy (ERT) group (OVX+E2), and ovariectomy, ERT plus neurokinin 1 receptor (NK1R) agonist (OVX+E2+G). Serum E2, body, and uterus weight were recorded. Immunohistochemistry study and quantitative real-time PCR were used for SP, NK1R, IL-1β, IL-6, and TNF-α examination and comparison in IVD at protein and gene levels. After OVX, the gene and protein expression of TNF-α, IL-1β, IL-6, SP, and NK1R in NP cells significantly increased compared with the sham group. ERT can reverse these impacts. ERT plays anti-inflammatory and anti-hyperalgesic roles in IDD of OVX mice. The estrogen-induced changes of the pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6, are significantly inhibited by NK1R agonists. SP may be a mediator of estrogen regulating pro-inflammatory factors in IDD. Estrogen may affect IVD inflammation through two ways: one is to directly affect the level of pro-inflammatory cytokines and the other is by means of modulation of SP.

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Funding

This work was funded by the National Natural Science Foundation of China (81400910, 81772292, and 81270027).

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Authors and Affiliations

  1. Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Er Lu, Shanghai, 200025, China

    Xiao-Xing Song, Yan Luo & Bu-Wei Yu

  2. Department of Spinal Surgery, Peking University People’s Hospital, Peking University, Beijing, 100044, China

    Lin-Yu Jin

  3. Department of Spine Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630, Dongfang Rd, Shanghai, 200127, People’s Republic of China

    Xin-Feng Li

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  1. Xiao-Xing Song
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Correspondence to Xin-Feng Li or Bu-Wei Yu.

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Xiao-Xing Song and Lin-Yu Jin are co-first authors

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Song, XX., Jin, LY., Li, XF. et al. Substance P Mediates Estrogen Modulation Proinflammatory Cytokines Release in Intervertebral Disc. Inflammation 44, 506–517 (2021). https://doi.org/10.1007/s10753-020-01347-1

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