Biomedical Engineering Reference
In-Depth Information
)
35
factors for type-I interferons (Ifn
α
, Ifn
β
, Ifn
κ
, and Ifn
ω
as well as members
of the families of nuclear factor-
B and AP1 Activator protein.
Excessive TLR-mediated inflammation is avoided after TLR4-mediated NF
κ
κ
B1
.
36
activation by a negative feedback based on tripartite-motif protein TRIM30
α
pathway.
37
Agent
TRIM30
α
binds
to
MAP3K7
in
the
TLR-NF
κ
B
Protein
TRIM30
α
associates
with
and
degrades
MAP3K7-interacting
proteins
MAP3K7IP2
38
MAP3K7IP3,
39
and
hence
reducing
production
of
NF
κ
B-
dependent
cytokines
TNF
and
IL6
and
impeding
secondary
stimulation
of
immunocytes [
1457
].
Chemokine-binding protein CCBP2,
40
also called CCR9 (GPR28) and CCR10
(GPR2), is required in inflammation [
1458
]. In case of CCBP2 deficiency, an
excessive concentration of residual chemokines induces an inflammatory pathology.
Chronic inflammation, characterized by numerous CD4
+
T lymphocytes and
macrophages, can lead to fibrosis and granuloma.
Toll-like receptors can interact with caveolae. For example, TLR4 connects to
caveolin-1 due to heme oxygenase-1 and carbon monoxide to reduce the production
of tumor-necrosis factor-
α
and interleukin-6 in macrophages [
878
].
11.5.6.2
Cytokines and Chemokines
Recruitment of circulating leukocytes with adhesion, chemotaxis, and cellular
activation stages requires cell adhesion molecules, chemokines (CCL2 and gmCSF),
and matrix degradation. Chemokines, such as CCL2 and CXCL8 (interleukin-8),
attract circulating leukocytes to the inflammation site. Once they have entered the
35
Receptors TLR3 and TLR4 activate IRF3; TLR7, TLR8, and TLR9 stimulate IRF7. Nine mem-
bers of the interferon-regulatory factor family bind to interferon-stimulated response elements.
Expression of several IRFs is induced by interferons and cytokines. Interferon-regulatory factors
are also regulated by post-translational modification. Phosphorylation of IRF3 and IRF7 by kinases
TBK1 and IKK
leads to the formation of dimers and nuclear translocation to regulate the
production of interferon-I in response to TLR activation. Interferon produced by stimulated TLRs
triggers an autocrine loop when it binds to cognate receptor (heterodimer made of interferon-
α
and -
[IfnaR2] chains) and activates the interferon-stimulated
gene factor ISGF3 complex (heterotrimer of IRF9, STAT1 and STAT2). Trimer ISGF3 also binds
to interferon-stimulated response elements. In addition, IRF1 regulates the synthesis of inducible
nitric oxide synthase in macrophages.
36
Members of the TRIM family regulate innate immunity. Many TRIM proteins have an antiviral
function, such as TRIM5
α
, TRIM25, TRIM28, etc. Synthesis of TRIM30
α
depends on NF
κ
B
factor.
37
Enzyme MAP3K7 is recruited to TRAF6 via MAP3K7-interacting protein MAP3K7IP2 and
MAP3K7IP3 for activation. The TRAF6-MAP3K7-MAP3K7IP2/3 complex recruits and activates
the IKK complex (MAP3K7 phosphorylates IKK
β
(and -
ω
) receptor
α
[IfnaR1] and
β
β
) to liberate NF
κ
B from I
κ
B inhibitor.
38
A.k.a. TGF
-activated kinase (TAK)-binding protein TAB2.
39
A.k.a. TAB3.
40
A.k.a. D6 chemokine receptor.
β
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