An Update on the Multifaceted Role of NF-kappaB in Endometriosis

Abstract

Endometriosis remains a common but challenging gynecological disease among reproductive-aged women with an unclear pathogenesis and limited therapeutic options. Numerous pieces of evidence suggest that NF-κB signaling, a major regulator of inflammatory responses, is overactive in endometriotic lesions and contributes to the onset, progression, and recurrence of endometriosis. Several factors, such as estrogen, progesterone, oxidative stress, and noncoding RNAs, can regulate NF-κB signaling in endometriosis. In the present review, we discuss the mechanisms by which these factors regulate NF-κB during endometriosis progression and provide an update on the role of NF-κB in affecting endometriotic cells, peritoneal macrophages (PMs) as well as endometriosis-related symptoms, such as pain and infertility. Furthermore, the preclinical drugs for blocking NF-κB signaling in endometriosis are summarized, including plant-derived medicines, NF-κB inhibitors, other known drugs, and the potential anti-NF-κB drugs predicted through the Drug-Gene Interaction Database. The present review discusses most of the studies concerning the multifaceted role of NF-κB signaling in endometriosis and provides a summary of NF-κB-targeted treatment in detail.

Keywords: NF-κB; endometriosis; peritoneal macrophage.

Figure 1

A simplified view of the structure and transduction process of NF-κB. (A) Structures of the members of the NF-κB signaling pathway. ① The NF-κB superfamily contains five members: RelA (p65), RelB, c-Rel, NF-κB1 (p105/p50), and NF-κB2 (p100/p52). p50 and p52 are shorter forms processed by p105 and p100, respectively. All members share a Rel homology domain (RHD), which contains two specific DNA-binding domains (DBDs) and a nuclear localization sequence. One of the DBDs is engaged in DNA recognition, and the other is involved in dimerization. ② The IκB family contains the three most important members: IKBα, IKBβ, and IKBγ. ③ The IKK complex contains the three most important members. GRR: glycine-rich region; ANK: ankyrin repeats; DD: death domain; TAD: transcription activation domain; LZ: leucine zipper domain; KD: kinase domain; HLH: helix-loop-helix domain; NBD: NEMO-binding domain; MOD/UBD: minimal oligomerization domain/ubiquitin-binding domain; ZF: zinc finger domain. (B) NF-κB signaling is activated in endometriotic cells. Stimuli, such as TNF-α and IL1, activate the IKK complex, triggering IKB phosphorylation and its subsequent proteasomal degradation. The RelA/p50 heterodimers then translocate to the nucleus and elicit transcriptional activity. Estrogen, progesterone, oxidative stress, and ncRNAs are the key regulators of NF-κB signaling, and the effects of estrogen on NF-κB signaling are controversial. Activation of the downstream genes of NF-κB signaling induces inflammatory responses and supports the survival, adhesion, migration, and invasion of endometriotic cells during endometriosis development.

Figure 2

NF-κB and estrogen in endometriosis. In endometriotic cells, estrogen can activate NF-κB signaling by activating CXCL12/CXCR4, PI3K/Akt, and TSLP signaling, and low REA expression also contributes to the activation of the estrogen/NF-κB axis. Estrogen-stimulated NF-κB activity further activates Akt and ERK signaling, represses PTEN expression, and induces production of the proinflammatory cytokines CCL2 and IL8. In addition, estrogen can inhibit NF-κB signaling in endometriotic cells by repressing AGTR1 expression. In peritoneal macrophages, estrogen/ERβ signaling can inhibit NF-κB activation and further inhibit NOS production.

Figure 3

NF-κB and oxidative stress in endometriosis. Oxidative stress induces NF-κB activation in endometriotic cells through iron overload and by activating the HMGB-1/TLR4 and estrogen/ERα pathways. HNF1β, as a coactivator for NF-κB, can activate NF-κB to protect endometriotic cells against oxidative damage. NF-κB activation in endometriotic cells may also induce the production of pro-oxidants (iNOS and NO) and reduce antioxidant enzymes (SOD, GPx, HO, and CAT). In peritoneal macrophages, estrogen/ERβ signaling can inhibit the NF-κB/NOS/NO axis and may alleviate oxidative stress.

Figure 4

NF-κB and macrophages in endometriosis. (A) NF-κB signaling contributes to the crosstalk between peritoneal macrophages (PMs) and endometriotic cells. The IL6/JNK/CCL17/CCR4 axis induces NF-κB activation in PMs, which then promotes IL6 production and forms a positive loop. In addition, IL1β and exosome-derived miR-22-3p secreted by PMs induce NF-κB activation in endometriotic cells, which may promote secretion of the proinflammatory cytokines RANTES and MIF. (B) NF-κB signaling affects PM polarization in the endometriotic milieu. Tregs and estrogen/ERβ signaling induce M2 macrophage polarization and endometriotic cell proliferation by repressing NF-κB in monocytes and activating NF-κB in endometriotic cells. Telocytes promote M1 macrophage polarization while inhibiting endometriotic cell proliferation and mitochondria-mediated PM apoptosis by activating NF-κB in PMs.

Figure 5

Potential interactions between drugs and key NF-κB signal-related genes, RELA and NFKB1. Drugs with an interaction score ≥ 0.2 were screened out. Triangles with sizes from small to large and colors from light to dark represent interaction scores from low to high.