Canonical, Non-Canonical and Atypical Pathways of Nuclear Factor кb Activation in Preeclampsia

Abstract

Although higher nuclear factor κB (NFκB) expression and activity is observed in preeclamptic placentas, its mechanism of activation is unknown. This is the first study to investigate whether the canonical, non-canonical, or atypical NFκB activation pathways may be responsible for the higher activation of NFκB observed in preeclamptic placentas. The study included 268 cases (130 preeclamptic women and 138 controls). We studied the expression of the genes coding for NFκB activators (NIK, IKKα, IKKβ, and CK2α) and inhibitors (IκBα and IκBβ) using RT-PCR in real time. The RT-PCR results were verified on the protein level using ELISA and Western blot. To determine the efficiency of the pathways, the ratios of activator(s) to one of the inhibitors (IκBα or IκBβ) were calculated for each studied pathway. The preeclamptic placentas demonstrated significantly lower IKKα and CK2α but higher IκBα and IκBβ protein levels. In addition, the calculated activator(s) to inhibitor (IκBα or IκBβ) ratios suggested that all studied pathways might be downregulated in preeclamptic placentas. Our results indicate that preeclamptic placentas may demonstrate mechanisms of NFκB activation other than the canonical, non-canonical, and atypical forms. In these mechanisms, inhibitors of NFκB may play a key role. These observations broaden the existing knowledge regarding the molecular background of preeclampsia development.

The Role of NF-κB in Uterine Spiral Arteries Remodeling, Insight into the Cornerstone of Preeclampsia

“…There are three known NF-κB activation pathways: canonical, non-canonical, and atypical [ 10 , 11 , 12 , 13 ].…”

“…The canonical pathway leads to activation of NF-κB through degradation of IκBs by IKK complex [ 10 , 11 , 12 ]. The activators of this pathway are interleukin 1 (IL-1) and a vast number of different damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), such as high-mobility group box 1 (HMGB1), fibrinogen, extracellular DNA, ATP and histones, glycans, flagellin, lipoteichoic acid, etc.…”

“…The non-canonical pathway can be activated by the tumor necrosis factor (TNF), B-cell activating factor (BAFF), CD40 ligands, or virus RNA [ 9 , 12 , 14 ]. Activated BAFF receptor (BAFFR), CD40, lymphotoxin β receptor (LTβR), or receptor activator for NF-κB (RANKL) associates with TNF receptor associated factors (TRAFs) complexes, which in turn release the NF-κB-inducing kinase (NIK) [ 17 ].…”

“…The atypical pathway is not one mechanism of NF-κB activation, but rather a term used for any of them that is different from canonical and non-canonical pathways and which is often not fully comprehended [ 12 , 13 ]. However, most often it involves casein kinase 2 (CK2), which is activated by reactive oxygen species, hypoxia, UV, or DNA damage phosphorylase IκBs, leading to its degradation in proteasome and release of NF-κB [ 12 , 13 ]. However, the exact mechanism of this process is unknown.…”

Nerve Growth Factor (NGF) modulates in vitro induced myofibroblasts by highlighting a differential protein signature

“…Some open questions still persist (1) as in vitro study on TGFβ1-induced myoFBs, and as known TGFβ1 does not represent the lone differentiating factor in vivo and other soluble mediators can trigger this differentiation; (2) the trkA NGFR /p75 NTR heterodimer distribution on cell membrane, as other trkA NGFR /trkA NGFR and p75 NTR /p75 NTR homodimers can also occur influencing the cellular pathway and finally (3) this NGF-driven p65 NFkB translocation could result in three different pathways (the canonical, the non-canonical, and the atypical one) depending on various upstream activating signals (TNFα, Interleukins, LPS/LT, UV and NO), influencing the entity of Bcl2:Bax ratio 42 . On the contrary, the possibility to use topical NGF will reduce all the disappointed effects played by the circulating addition of NGF.…”