Inhibitory action of Lipoxin A4 on PDGF, EGF and LTD4
Control of inflammation is crucial to prevent damage to the host during infection.
Lipoxins, which are metabolites of trihydroxytetraene-containing arachidonic acid, are
crucial modulators of proinflammatory response. In the absence of Lipoxin
A4 biosynthetic pathways, uncontrolled inflammation during infection is
lethal, even in the case of pathogen clearance , , , .
Lipoxin A4 exerts its action via an interaction with its
cognate G protein-coupled receptor (GPCR), Formyl peptide receptor-like 1
(FPRL1) , , , .
Lipoxins display potent antiinflammatory action, including attenuation of neutrophil
migration and reactive oxygen species (ROS) production that mediates the switch to
chronic inflammation and promotes resolution , , , , .
FPRL1 interaction with Lipoxin A4
and aspirin-triggered lipoxins on neutrophils regulates the polyisoprenyl
phosphate signaling pathway. FPRL1 activation by lipoxins
reverses Leukotriene B4-initiated polyisoprenyl phosphate remodeling, leading to
accumulation of Presqualene diphosphate, a potent negative
intracellular signal in neutrophils that inhibits phospholipase D 1
(PLD1) and superoxide anion generation , , , .
In monocytes and macrophages (but not neutrophils), Lipoxin
A4, can induce Ras homolog gene family, member A
(RhoA)-dependent cytoskeleton reorganization, via
FPRL1 / G-protein alpha-i family
/ Adenylate cyclase pathway and inhibition of
Cyclic AMP (cAMP). Lipoxin-induced migration of monocytes
and macrophages may contribute to the resolution of inflammation , .
Lipoxin A4 also acts as a partial agonist to mediate the
bioactions in several tissues and cell types other than leukocytes, via interactions with
two GPCRs, Cysteinyl Leukotriene Receptor 1 and 2 (CysLT1
and CysLT2) , .
Lipoxin A4 blocks Leukotriene D4
(LTD4) actions and also competes for specific
LTD4 binding on mesangial cells  and human
umbilical vein endothelial cells . Lipoxin A4
and LTD4 bind and compete with essentially
equal affinity at CysLT1 and CysLT2
, , , , , providing a molecular basis for Lipoxin
serving as a local damper of both vascular CysLT1 /
CysLT2 signals as well as Lipoxin/
FPRL1-regulated neutrophil trafficking .
In human renal mesangial cells, Lipoxin A4 has been shown
to inhibit Platelet-derived growth factor beta (PDGF-B) and
LTD4-stimulated cell proliferation.
LTD4 transactivates Platelet-derived growth factor receptor
beta (PDGF-R-beta) via CysLT2 /
G-protein alpha-q/11 / c-Src
signaling. Lipoxin A4 inhibits
LTD4-induced phosphorylation of
PDGF-R-beta by c-Src and also
inhibits PDGF-B activation of
PDGF-R-beta and proliferative responses to
Lipoxin A4 / FPRL1 signaling
is also coupled with reactivation of Protein tyrosine phosphatase
SHP-2, that specifically dephosphorylates the recruitment
sites of the Phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PI3K
reg class IA (p85)) on the platelet-derived growth factor receptor beta
(PDGF-R-beta) and Epidermal growth factor receptor
(EGFR) . Platelet-derived growth factor beta
and Epidermal growth factor (EGF)-activated
EGFR undergo autophosphorylation at multiple tyrosine
residues followed by association with numerous signal transduction proteins that include
Phospholipase C gamma 1 (PLC-gamma 1), PI3K
reg class IA (p85) and SHP-2.
H2O2 can oxidatively inactivate
SHP-2, within the microenvironment of
PDGF-R-beta. Activation of the lipid raft-bound
FPRL1 induces recruitment to and activation/reactivation of
SHP-2 through direct stimulation of
SHP-2 and/or indirectly by attenuating
H2O2 production. Although Peroxiredoxin 2
(PRDX2) allows oxidatively inactivated
SHP-2 to be reactivated by removing endogenous
H2O2 , , ,
Lipoxin A4 attenuation of H2O2
production and hence activation of SHP-2 has
been shown to be independent of PRDX2 .
In addition to inducing G-protein-coupled receptor FPRL1
signaling, lipoxins, can also activate a nuclear receptor Aryl hydrocarbon receptor
(AHR) , which triggers expression of
Suppressor of cytokine signaling 2 (SOCS2). Both receptors,
FPRL1 and AHR,
are involved in SOCS2 induction in dendritic
cells . SOCS2-deficient cells are
hyper-responsive to microbial stimuli, as well as refractory to the inhibitory actions of
Lipoxin A4. Upon infection with an intracellular pathogen,
SOCS2-deficient mice had uncontrolled production of
proinflammatory cytokines, decreased microbial proliferation, aberrant leukocyte
infiltration and elevated mortality. SOCS2 is a crucial
intracellular mediator of the anti-inflammatory actions of lipoxins , .
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