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Orekhov et al. Vessel Plus 2019;3:10 I http://dx.doi.org/10.20517/2574-1209.2019.04 Page 9 of 20

dependent pathway controls induction of Type I IFNs and IFN-responsive genes. IκB kinase (IKK) mediates
[92]
inhibitory IκB phosphorylation and depression of NF-κB . LPS also induces the expression of IL-1β and
[93]
TNF-α that support and propagate NF-κB signaling in an autocrine manner . LPS activates various
MAPKs that induce AP-1. The catalytic subunit of NF-κB RelA (p65) controls MAPK-independent IKKε-
mediated activation of AP-1 through phosphorylation of c-Jun and subsequent removal of the nuclear
[94]
receptor corepressor (NCoR) from the target promoters . NF-κB facilitates AP-1-mediated transcription
thereby promoting the integration of NF-κB and AP-1-dependent expression of pro-inflammatory genes
[90]
including iNOS, CCL2, CCL5, and Cox-2 .

The homodimerization of NF-κB1 (p50) and NF-κB2 (p52) leads to generation of transcriptional repressors,
since both molecules lack the transcription activation domain presented in the other members of the NF-
[95]
κB family: RelA, RelB, and c-Rel . The inhibitory subunit p50 binds to the promoters of NF-κB-inducible
inflammatory genes and blocks their transcription. Macrophages lacking p50 develop enhanced M1-
polarized response to stimulation with LPS [79,96] . In macrophages, p50 deficiency is associated with altered
recruitment of RNA polymerase II to M2-specific promoters such as CCL17 and arginase-1 whereas
[95]
transcriptional activation of M1-specific promoters including iNOS, IFN-β, and TNF-α is up-regulated .
Regulation of NF-κB family transcriptional activity plays a central role in M1-M2 switching and macrophage
polarization towards either anti-inflammatory or pro-inflammatory phenotype.

AP-1
AP-1 recruitment is mediated by the Jnk-dependent mechanism in response to inflammatory stimuli. The
[90]
spectrum of AP-1 transcription targets overlaps substantially with that of NF-κB . AP-1 comprises a group
of heterodimeric or homodimeric basic leucine zipper (bZIP) transcription factors composed of proteins
[90]
that belong to the c-Fos, c-Jun, ATF, and JDP families that recognize DNA sequence ATGAGTCAT . Of
possible heterodimeric AP-1 variants, c-Fos/c-Jun heterodimers have the highest affinity for AP-1 binding
[97]
sites . Jnk-dependent phosphorylation of c-Jun subunit induces formation of the transcriptionally active
[98]
c-Jun/c-Fos heterodimer .
In macrophages, TLR-4 stimulation with LPS induces TNF-α production, which provides a positive feedback
for maintaining transcriptional activity of AP-1 through binding to the receptor TNFR1 and activation of
[99]
JNK . In M1 polarized macrophages, AP-1 and NF-κB share many signaling networks and transcription
targets that can suggest a concomitant stimulation and cooperative activity of both factors [100] . Since both
AP-1 and NF-κB can be activated LPS, the regulatory regions of many LPS-inducible genes such as CXCL2,
CXCL9, CXCL10, CCL4, and iNOS contain coupled AP-1/κB binding elements.

LPS can also induce the removal of transcription repressor complexes from mixed AP-1/κB sites to initiate
transcription. In resting macrophages, the activity of promoters of a variety of inflammatory genes is blocked
by repressor complexes. For example, NCoR associates with silencing mediator of retinoic or thyroid hormone
receptors (SMRT; also known as NcoR2) to form a corepressor complex, which binds either to c-Jun or p50 and
[101]
inhibits transcription from AP-1/κB sites . LPS-dependent stimulation leads to the recruitment of p65 that
mediates activation of IKK-ε followed by inhibitory phosphorylation of NcoR and derepression of adjacent AP-1/
[94]
κB sites . LPS can also induce the removal of corepressor complexes through ubiquitylation/proteosomal-
dependent degradation [102,103] . TLR2, which binds various lipid- and carbohydrate-containing microbial products
and induces AP-1 and NF-κB activation, stimulates Ca /calmodulin-dependent protein kinase II (CaMKII)-
2+
dependent phosphorylation of the TBLR1 component of NCoR complexes which leads to the dissociation of the
[94]
NcoR/NcoR2 corepressor complex . Therefore, regulation of the NcoR/NcoR2 checkpoint plays a central role
in TLR-2 and TLR-4-induced activation of expression of pro-inflammatory genes.

HYPOXIA-INDUCIBLE FACTORS