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TLR-4/TLR-9-dependent NF-κB activation by binding to p65 that in turn prevents the formation of a
transcriptionally active complex NF-κB/IRF3 [117] . The association of SHR with p65 disrupts the recruitment
of the positive transcription elongation factor b, which also interrupts fast induction of NF-κB-dependent
transcription [118] . Transrepressor activity of SHRs is applicable to the negative regulation of AP-1. SHR
binding to c-Fos abolishes the formation of an active AP-1 complex [119] .

SHR interacts with steroid receptor coactivator-2 (SRC-2, also known as a nuclear receptor coactivator
2, NCoA2). NCoA2 possesses intrinsic histone acetylase activity, which makes downstream DNA more
accessible to transcription [120] . NCoA2/SHR complex can also act as a transcription repressor. For example,
recruitment of this complex to HRE sites of NF-κB-inducible genes blocks their transcription [121] . However,
systemic challenge with LPS can depress some NF-κB target genes in mouse NcoA2-deficient macrophages
and induce LPS-dependent inflammatory responses [122] . Together, these observations suggest for potent anti-
inflammatory effects of glucocorticoids and SHRs and their marked role in the anti-inflammatory activation
of macrophages.

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARS)
The family of peroxisome proliferator-activated receptors (PPARs) comprises a broadly expressed group
of nuclear factors. PPAR-γ is preferentially expressed in the adipose tissue, adrenal gland, and spleen. In
macrophages, PPAR-γ acts as a key anti-inflammatory factor, which blocks activation of major effector
[123]
contributors to M1 polarization such as NF-κB, AP-1, and STAT . Transcriptional suppression mediated by
PPAR-γ is based on stabilization of transcription corepressor complexes at the promoters of the inflammatory
genes. PPAR-γ sumoylation targets this factor to NCoR and histone deacetylase-3 (HDAC3)-containing
corepressor complexes. This protects the corepressor complex from the ubiquitylation/19S proteasome-
dependent degradation and stabilizes repression of inflammatory genes [124] . It was demonstrated that PPAR-
γ-dependent stabilization of the inhibitory complex at the NF-κB-inducible promoters in apoptotic cells
facilitates their further clearance by macrophages during the inflammation resolution [102] .

Basal expression of PPAR-γ is observed in non-activated macrophages, but it could be significantly up-
regulated in response to Th2 cytokines IL-4 and IL-13, indicating for a role of PPAR-γ as M2 polarization
factor [125] . IL-4-induced STAT-6 assembles with PPAR-γ that in turn results in enhanced transcription of fatty
acid binding protein 4 (FABP4) and other PPAR-γ target genes [126] . Inflammatory cytokines inhibit PPAR-γ-
dependent gene transcription by functional inactivation of this factor, while PPARγ remains associated with
the DNA though unable to initiate gene expression [127] .

The activity and expression of PPAR-γ is regulated metabolically. PPAR-γ induces the expression of a set of
genes involved in fatty acid catabolism and oxidation, a major metabolic energy source in M2 macrophages.
Free fatty acids are well known as PPAR-γ agonists. Indeed, PPAR-γ-mediated up-regulation of FABP4,
a fatty acid carrier, increases influx of endogenous fatty acids to macrophages and further stimulates
PPAR-γ activity. In IL-4 stimulated macrophages, FABP4 inhibition leads to the down-regulation of PPAR-γ
activity and suppresses formation of foam cells in hyperlipidemic conditions [128] . Deficiency of PPAR-γ in
macrophages prevents generation of the M2 phenotype, as was shown in PPAR-γ-deficient mice, which were
prone to obesity and glucose resistance when fed a fat-rich diet [129] . Since macrophages play a prominent role
in lipid transport and metabolism, PPAR-γ-mediated alternative activation of macrophages plays a protective
role against obesity-induced adipose inflammation and impaired glucose metabolism in the skeletal
muscle [129-131] . Synthetic PPAR-γ agonists showed their efficiency in the treatment of metabolic diseases such
as diabetes, atherosclerosis, and obesity, where inflammatory activation of macrophages leads to detrimental
chronic tissue inflammation [132,133] .

PPAR-δ, another member of the PPAR family of transcriptional regulators, cooperates with PPAR-γ in