Disease relevance of Pla2g4a

• Cytosolic phospholipase A2 enzymes are not required by mouse bone marrow-derived macrophages for the control of Mycobacterium tuberculosis in vitro [1].
• Cytosolic phospholipase A2 alpha-deficient mice are resistant to experimental autoimmune encephalomyelitis [2].
• Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2 [3].
• Thus, the inhibition of cPLA2-initiated pathways may provide a therapeutic approach to acute lung injury, for which no pharmaceutical agents are currently effective [4].
• Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A2 [4].

High impact information on Pla2g4a

• A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with homology to PKC and GAP [5].
• We find that normal growth of skeletal muscle, as well as normal and pathologic stress-induced hypertrophic growth of the heart, are exaggerated in Pla2g4a-/- mice, which lack the gene encoding cytosolic PLA2 [6].
• Deletion of cytosolic phospholipase A2 promotes striated muscle growth [6].
• The mechanism underlying this phenotype is that cytosolic PLA2 negatively regulates insulin-like growth factor (IGF)-1 signaling [6].
• Generation of arachidonic acid by the ubiquitously expressed cytosolic phospholipase A2 (PLA2) has a fundamental role in the regulation of cellular homeostasis, inflammation and tumorigenesis [6].

Chemical compound and disease context of Pla2g4a

• We found that disruption of the gene encoding cPLA2 significantly reduced pulmonary edema, PMN sequestration and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration [4].
• The release of [3H]-AA following treatment with UTP and thapsigargin were non-additive, totally abolished in the Ca2+-free buffer, BAPTA (30 microM)-containing buffer or in the presence of the cPLA2 inhibitor MAFP (50 microM), and inhibited by pretreatment of cells with pertussis toxin (100 ng ml(-1)) or 4-bromophenacyl bromide (100 microM) [7].
• Although Group IV cytosolic phospholipase A2 (cPLA2) in astrocytes has been implicated in a number of neurodegenerative diseases, mechanisms leading to its activation and release of arachidonic acid (AA) have not been clearly elucidated [8].
• In addition to tyrosine phosphorylation, cPLA2 catalytic activation requires serine phosphorylation by p42 mitogen-activated protein (MAP) kinase and possibly pertussis toxin-sensitive G-protein coupling [9].

Biological context of Pla2g4a

• These results raised the possibility that caveolin-1, via the inhibition of cPLA2 enzymatic activity, may interfere with synaptic facilitation and long term potentiation formation in the hippocampus [10].
• Inhibition of cPLA2 in wild-type and CCSP-/- mice ventilated at high PIP for 4 h significantly reduced bronchoalveolar lavage albumin and total protein and lung wet-to-dry weight ratios compared with vehicle-treated mice of the same genotype [11].
• This study suggests that cPLA2 is a necessary component in the pathways leading to ceramide accumulation and cell death [12].
• The results suggest that garcinol modulates arachidonic acid metabolism by blocking the phosphorylation of cPLA2 and decreases iNOS protein level by inhibiting STAT-1 activation [13].
• This effect seemed to be due to down-regulation of cPLA2 [14].

Anatomical context of Pla2g4a

• This study in Pla2g4a-/- mice, together with the results of differential blastocyst transfers in wild-type mice provides the first evidence for a novel concept that a short delay in the initial attachment reaction creates a ripple effect propagating developmental anomalies during the subsequent course of pregnancy [15].
• Cytosolic phospholipase A2 is essential for both the immediate and the delayed phases of eicosanoid generation in mouse bone marrow-derived mast cells [16].
• Arachidonic acid release from wild-type mouse lung fibroblasts (MLF+/+) was stimulated by serum, A23187 plus phorbol-myristate acetate (PMA), and lysophosphatidic acid (LPA) plus platelet-derived growth factor, but was > or = 80% lower from cPLA2 alpha-deficient MLF (MLF-/-) [17].
• The variant cell line C12, which lacks cPLA2, is resistant to the cytotoxic action of TNFalpha [12].
• Stimulated peritoneal macrophages from cPLA2-/- animals did not produce prostaglandin E2 or leukotriene B4 or C4 [3].

Associations of Pla2g4a with chemical compounds

• Disruption of the gene encoding cPLA(2) (Pla2g4a) attenuated IPF and inflammation induced by bleomycin administration [18].
• For the immediate phase, quantitative analysis of the products of the 5-lipoxygenase pathway showed that gene disruption of cPLA2 prevented the provision of arachidonic acid substrate for biosynthesis of proximal intermediates [16].
• Prostaglandin E2 amplifies cytosolic phospholipase A2- and cyclooxygenase-2-dependent delayed prostaglandin E2 generation in mouse osteoblastic cells. Enhancement by secretory phospholipase A2 [19].
• These results demonstrate a role for cPLA2 in mouse lung tumorigenesis that may be mediated by decreased prostaglandin synthesis [20].
• Thus, kinetic, pharmacologic, and genetic analyses suggest that an inducible, heparin-sensitive PLA2, rather than cPLA2, provides arachidonic acid to concomitantly induced PGHS-2 for delayed-phase PGD2 biosynthesis in activated BMMC [21].

Enzymatic interactions of Pla2g4a

• In peritoneal macrophages, ERK kinase activity was stimulated and cPLA2 was phosphorylated and activated in response to CSF-1 [22].

Regulatory relationships of Pla2g4a

• A peptide corresponding to the scaffolding domain of caveolin-1 (Cav-(82-101)) dramatically inhibited cPLA2 activity in purified hippocampal synaptoneurosomes [10].
• The expression of brain cyclooxygenase-2 is down-regulated in the cytosolic phospholipase A2 knockout mouse [23].
• We propose that mechanical activation of the cPLA2 pathway contributes to acute high PIP-induced lung injury and that CCSP may reduce this injury through inhibition of the cPLA2 pathway and reduction of proinflammatory products produced by this pathway [11].
• Addition of partially purified sPLA2 from BMMC enhanced cPLA2 activity and AA release [24].
• These cells exhibit increased basal PG production, which is due to a constitutively stimulated cytosolic phospholipase A2 and enhanced basal expression of the remaining COX isozyme [25].

Other interactions of Pla2g4a

• Our results raise the possibility that deprivation of COX-2 of its substrate by the suppression of cPLA2 mRNA expression is an additional mechanism used by NSAIDs to inhibit tumorigenesis [26].
• The lack of sPLA2IB, sPLA2IIA, and sPLA2V mRNA expression in both NIH3T3 and MC3T3E1 cells suggests that cPLA2 is the most likely enzyme that catalyzes the release of AA, the rate-limiting substrate of COX for the production of PGs [26].
• The results demonstrate a primary role for cPLA2 alpha in providing arachidonic acid for PGE2 production in mouse lung fibroblasts and support a role for this pathway in regulating collagen production [17].
• These data suggest that sPLA2 mediate the selective release of AA by binding to cell surface receptors and then inducing signal transduction events that lead to cPLA2 activation [24].
• In sum, there is no simple relationship between the ability of M phi s to release and metabolize AA, and the expression of cPLA2 or COX isoforms [27].

Analytical, diagnostic and therapeutic context of Pla2g4a

• In contrast, cPLA2 was shown to be expressed and activated in thymocytes and immature B cells under conditions in which ligation of the Ag receptors led to growth arrest and/or apoptosis [28].
• Using high-resolution confocal microscopy of the human A549 lung epithelial cell line, we show that cPLA2-alpha relocates from the cytosol and nuclei to a juxtanuclear region following stimulation with the Ca2+ ionophore A23187 [29].
• Immunohistochemistry and real-time RT-PCR revealed elevated cPLA2 protein and its mRNA levels in the lumbar spinal cord of mutant SOD1 mice [30].
• Further, both the amount of cPLA2 (as assessed by Western blotting) and the release of AA resulting from direct activation of cPLA2 increased fourfold in cells treated with IL-1beta [31].
• Gene targeting studies show that, in the knockout mice of steroid 5alpha-reductase type 1 gene, prostaglandin F2alpha receptor gene and cytosolic phospholipase A2 gene, parturition was severely disturbed, although live offspring were delivered by Caesarean section [32].

References