Biomedical Engineering Reference
In-Depth Information
Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene have
been described to be involved in three different chronic autoinflammatory diseases
[12]. CIAS proteins have been reported to inhibit nuclear translocation of p65 in
monocytes, which implies that p65-inhibition may contribute to the induction of the
chronic inflammatory phenotype; however, it has to be kept in mind that CIAS-
mutations can also lead to increased processing of IL-1
β
-precursor into mature
IL-1
, a major proinflammatory cytokine [13].
Recently, a new family of NF-
β
B inhibitory proteins has been identified. The
first family member, Murr1, was identified due to its involvement in copper metab-
olism [14
,
15]. Nine other family members have since been described, all of which
are characterized by a copper metabolism gene Murr1 domain (COMMD) that
functions as a homotypic protein-protein interaction domain [16]. COMMD1
through -10 form multimeric complexes, and several of them interact with and inhibit
NF-
κ
B. Murr1/COMMD1, the prototype of the family, does not inhibit nuclear
translocation of NF-
κ
B signaling at the nuclear level by
negatively regulating the association of p65 with chromatin. Co-IP experiments
showed that Murr1/COMMD1 interacts with p65, c-Rel, RelB, p100, and p105.
COMMD1
binds to the first 180 amino acids of the p65 Rel homology domain
(RHD) containing the DNA binding domain and thus may directly interfere with
binding to
κ
B, but rather inhibits NF-
κ
B sites.
15-Deoxy-
κ
-
12,14
-prostaglandin J
2
(15d-PGJ
2
), the ligand of the peroxisome pro-
liferator-activated receptor-
Δ
) transcription factor, is a recently discovered
prostaglandin that has been suggested to elicit an antiinflammatory response [17].
PPAR
γ
(PPAR
γ
is thought to be complexed in the cytosol to corepressor proteins but is
probably released from corepression by binding of 15d-PGJ
2
or other PPAR
γ
-ago-
nists such as thiazolidinediones (glitazones). It has been suggested that 15d-PGJ
2
inhibits NF-
γ
κ
B indirectly via PPAR
γ
by antagonizing the transcriptional activity of
NF-
κ
B [18]. The interference of PPAR
γ
(and other nuclear antagonists of NF-
κ
B
such as p53, ARF, Twists, and N-CoR) with NF-
B could be mediated by compe-
tition for histone acetyltransferase (HATs) or recruitment of HDACs to NF-
κ
κ
B
[19
,
20]. Additionally, 15d-PGJ
2
has been described to inhibit NF-
κ
B activity directly
by binding to IKK
β
via its cyclopentenone ring, thereby inhibiting IKK
β
activity
[21]. The same ring has also been reported to prevent NF-
B from binding to DNA
by modifying p65 and p50 [22]. Finally, it has been reported that 15d-PGJ
2
inhibits
the recruitment of CBP/p300, an essential cofactor for NF-
κ
κ
B's transcriptional
activity, to p65 [23]. At present, 15d-PGJ
2
and other PPAR
-agonists have been
shown to inhibit inflammation in murine models of arthritis, ischemia-reperfusion
injury, inflammatory bowel disease, Alzheimer's disease, and lupus nephritis [17],
which are all diseases in which NF-
γ
B is known to be chronically activated.
The nuclear protein RelA (p65)-associated inhibitor
(RAI), isolated from human
placenta, has been found to inhibit tumor necrosis factor (TNF)-induced NF-
κ
B
signaling by binding to p65 and preventing its DNA-binding. This 351 amino-acid,
40 kDa protein contains multiple ankyrin repeats, just as the I
κ
B family members,
but it does not contain a proline, glutamic acid, serine, and threonine (PEST)-region
[24]. Recently, it was shown that RAI is part of a larger protein (824 amino acids,
98 kDa) called NF-
κ
κ
B interacting protein1 (Nkip1), which is predominantly
