Biomedical Engineering Reference
In-Depth Information
Table 11.10.
Phosphoinositide 3-kinases in inflammation.
PI3K isoform
Stimulus
Effect
PI3K
c1δ
Ig receptors
Mastocyte degranulation
PI3K
c1γ
Chemokines,
Leukocyte migration
complement fragments,
bacterial products, etc.
GPCR, G
βγ
Mastocyte activation
protein kinase-C isoforms. Moreoevr, RhoA GTPase is activated by GDP-GTP
exchange factors, isoprenylated by geranylgeranyl pyrophosphate, and translocates
to the plasma membrane to reorganize the cytoskeleton and produce reactive oxygen
species.
In hepatocytes, activated PKC phosphorylates CARD and MAGuK domain-
containing protein CARMA3, a tissue-specific member of the MAGUK superfam-
ily. Scaffold CARMA3
P
complexes with B-cell lymphoma protein BCL10 and
mucosa-associated lymphoid tissue lymphoma translocation MALT1 to form the
CBM signalosome
. Activated MALT1 causes Lys63-linked ubiquitination of IKK
and cleaves the IKK inhibitor TNF
α
IP3 that deubiquitinates TRAF6, RIPK1, and
IKK
B is sequestered in the cytoplasm, both
the translocation and transactivation modules using the CBM signalosome and the
RhoA-MAP3K14 axis are involved in angiotensin-2 signaling [
1446
].
In vascular smooth myocytes, inactive NF
γ
. Therefore, in hepatocytes, where NF
κ
B is constitutively nuclear. The pre-
dominant signaling arises from the activation of the NF
κ
κ
B transactivation mod-
ule. Angiotensin-2 rapidly provokes NF
B activation, as RelA is phosphorylated
(Ser536) by MAP3K14 using the RhoA-NIK pathway [
1446
].
κ
11.5.6.8
Lipid Signaling
Lipid signaling contributes to inflammation and its deregulation to metabolic and
degenerative diseases and cancer. Inflammation is characterized by excess activation
of PI3K (Table
11.10
) and SphK pathways [
1465
]. Excess circulating fatty acids
cause long-term inflammation via Toll-like receptor TLR4, and production of
reactive oxygen species and activation of inflammatory kinase pathways (PKC,
IKK
β
).
11.5.6.9
Leukotrienes and Prostaglandins
The plasmalemmal, polyunsaturated fatty acid arachidonic acid forms potent lipid
mediators leukotrienes that are vasoconstrictors and prostaglandins (PG) that
are either vasoconstrictors or vasodilators (Chaps.
8
and
9
). Leukotrienes and
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