Pathway maps

Inhibitory action of Lipoxin A4 on PDGF, EGF and LTD4 signaling
Inhibitory action of Lipoxin A4 on PDGF, EGF and LTD4 signaling

Object List (links open in MetaCore):

PKA-cat , PLD1,, PI3K reg class IA (p85), EGF, , G-protein alpha-q/11, PRDX2, Presqualene diphosphate, SHP-2, RhoA, PDGF-B, EGFR, c-Src, Thioredoxin, PKA-reg, G-protein alpha-i family, Presqualene monophosphate, CysLT2 receptor, PDGF-R-beta, LTD4, Lipoxin A4 cytoplasm, cAMP, PLC-gamma 1, SOCS2, H(,2)O(,2) cytoplasm, Adenylate cyclase, CysLT1 receptor, Lipoxin A4 extracellular region, Oxidized thioredoxin, PPAPDC2, 3.1.3.-, FPRL1, AHR


Inhibitory action of Lipoxin A4 on PDGF, EGF and LTD4 signaling

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 [1], [2], [3], [4].

Lipoxin A4 exerts its action via an interaction with its cognate G protein-coupled receptor (GPCR), Formyl peptide receptor-like 1 ( FPRL1 ) [5], [6], [7], [8].

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 [9], [5], [6], [10], [8].

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 [11], [12], [10], [7].

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 [13], [6].

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 ) [14], [7]. Lipoxin A4 blocks Leukotriene D4 ( LTD4 ) actions and also competes for specific LTD4 binding on mesangial cells [15] and human umbilical vein endothelial cells [16]. Lipoxin A4 and LTD4 bind and compete with essentially equal affinity at CysLT1 and CysLT2 [17], [18], [19], [14], [5], 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 [7].

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 PDGF-B [20].

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 ) [21]. Platelet-derived growth factor beta ( PDGF-B )-activated PDGF-R-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 [22], [23], [24], Lipoxin A4 attenuation of H2O2 production and hence activation of SHP-2 has been shown to be independent of PRDX2 [21].

In addition to inducing G-protein-coupled receptor FPRL1 signaling, lipoxins, can also activate a nuclear receptor Aryl hydrocarbon receptor ( AHR ) [25], which triggers expression of Suppressor of cytokine signaling 2 ( SOCS2 ). Both receptors, FPRL1 and AHR, are involved in SOCS2 induction in dendritic cells [4]. 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 [4], [26].


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