Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 720

IgER
LAT

PI(3,4)P2 PIP3 PI(4,5)P2

SYK

NTAL

GRB2
GAB2

BTK

IP3

cytohesin−3

DAG

PLC

Ca

PI3K

PLD PKC

Cer

Sph

CerK

SphK

S1P C1P

PG

ABCc1

PLA2

PGh2S

LT

AA

mast cell

5LOx

PA PL

Fig. 11.2 Antigen receptor and lipid signaling in inflammation and allergy (Source: [ 1465 ]).
IgE-antigen complex binding to IgE receptors (IgER) primes IgER phosphorylation by membrane-
bound protein tyrosine kinases (i.e., Fyn). Subsequently, Syk, which is recruited to phosphorylated
IgE receptor, mediates the phosphorylation of adaptors, such as linker for activation of T cells
(LAT), non-T-cell activation linker (NTAL), and GRB2-associated binder (GAB2), which together
favors the recruitment of class-1A phosphoinositide 3-kinases. At the plasma membrane, PI3K
generates phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ) from PIP 2 lipid. PI3K relays signals

from not only the IgE receptor, but also the B-cell receptor and the T-cell receptor. Overstimulation
of immunocytes at low antigen concentrations is hindered by the SH2-domain-containing inositol
5-phosphatase-1 (SHIP1). Agent PIP 3 recruits proteins, such as Bruton tyrosine kinase (BTK),
phospholipase-C

δ

,
which cleaves PIP 2 into diacylglycerol (DAG) and IP 3 . Messenger IP 3 releases Ca 2 + from
cellular stores. Phospholipase-D (PLD) and sphingosine kinase (SphK) are activated when
PIP 3 concentration remains high. Activated SphKs generate phosphatidic acid (PA) and S1P
mediators. In addition, SphK reinforces Ca 2 + release that causes activation of mastocytes, hence
stimulating PKC, ceramide kinase (CerK), phospholipase-A2 (PLA2), 5-lipoxygenase (5LOx)
and prostaglandin-H2 synthase (PGh2S), and triggering degranulation of histamine-containing
granules and production of prostaglandins (PG) and leukotrienes (LT) from arachidonic acid (AA)
by PLA2, PGh2S, and 5LOx. Eicosanoids drive inflammation. Prostaglandins, leukotrienes, and
sphingosine 1-phosphate (S1P) exit the cell via cognate carriers, such as ATP-binding cassette
transporter ABCC1 for S1P, and act on G-protein-coupled receptors of neighboring cells that relay
signals to effectors, such as PLC

γ (PLC), and cytohesin-3 (an ArfGEF). Activated BTK phosphorylates PLC γ

enzymes. Eicosanoids and S1P act with chemokines,
cytokines, and histamine to promote constriction of downstream arteries and bronchi, dilation
of upstream arteries, and to increase vascular permeability and attract leukocytes. Ceramide
1-phosphate (C1P) is produced by CerK from ceramide (Cer).

β and PI3K γ

prostaglandins promote leukocyte chemotaxis. In particular, they are chemoattrac-
tants for neutrophils.
Eicosanoids — prostaglandins and leukotrienes — act via G-protein-coupled
receptors and intervene in inflammation and allergy (Fig. 11.2 ).
Prostanoids derive from unsaturated

6-fatty acids, such as arachidonic acid.
They produce inflammatory mediators. On the other hand, unsaturated

ω

ω 3-fatty

acids are a source for anti-inflammatory and homeostatic prostanoids.