Skip to main content
SpringerLink
Log in

Differential regulation of cPLA2 and iPLA2 expression in the brain

  • Review
  • Published:
Frontiers in Biology

Abstract

The phospholipase A2 (PLA2) family members are critical regulators of membrane structure and lipid composition and have been implicated in neuroinflammation, oxidative stress and neurodegeneration. Here, we review the published data describing regulation of cPLA2 and iPLA2 gene expression. Based on promoter sequence, cPLA2 expression can be regulated by glucocorticoid and pro-inflammatory cytokines, whereas transcription of iPLA2 can be controlled in response to sterol level. RNA degradation in 3′ UTR and epigenetic mechanisms may be involved in the regulation of cPLA2 and iPLA2 expression, respectively. MicroRNA target sequences lie within cPLA2 and iPLA2 mRNAs. Together, these findings indicate differential regulation of cPLA2 and iPLA2 expression. It is hoped that determination of diverse regulatory mechanisms of the PLA2 family may open new doors for development of novel therapeutic compounds that modulate PLA2 expression and function in the treatment of brain diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Adler D H, Cogan J D, Phillips J A 3rd, Schnetz-Boutaud N, Milne G L, Iverson T, Stein J A, Brenner D A, Morrow J D, Boutaud O, Oates J A (2008). Inherited human cPLA(2α) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction. J Clin Invest, 118(6): 2121–2131

    PubMed  CAS  Google Scholar 

  • Adler V, Yin Z, Tew K D, Ronai Z (1999). Role of redox potential and reactive oxygen species in stress signaling. Oncogene, 18(45): 6104–6111

    Article  PubMed  CAS  Google Scholar 

  • Alexandrov P N, Cui J G, Lukiw W J (2006). Hypoxia-sensitive domain in the human cytosolic phospholipase A2 promoter. Neuroreport, 17(3): 303–307

    Article  PubMed  CAS  Google Scholar 

  • Arai K, Ikegaya Y, Nakatani Y, Kudo I, Nishiyama N, Matsuki N (2001). Phospholipase A2 mediates ischemic injury in the hippocampus: a regional difference of neuronal vulnerability. Eur J Neurosci, 13(12): 2319–2323

    Article  PubMed  CAS  Google Scholar 

  • Bao S, Bohrer A, Ramanadham S, Jin W, Zhang S, Turk J (2006a). Effects of stable suppression of Group VIA phospholipase A2 expression on phospholipid content and composition, insulin secretion, and proliferation of INS-1 insulinoma cells. J Biol Chem, 281(1): 187–198

    Article  PubMed  CAS  Google Scholar 

  • Bao S, Song H, Wohltmann M, Ramanadham S, Jin W, Bohrer A, Turk J (2006b). Insulin secretory responses and phospholipid composition of pancreatic islets from mice that do not express Group VIA phospholipase A2 and effects of metabolic stress on glucose homeostasis. J Biol Chem, 281(30): 20958–20973

    Article  PubMed  CAS  Google Scholar 

  • Bickford J S, Newsom K J, Herlihy J D, Mueller C, Keeler B, Qiu X, Walters J N, Su N, Wallet S M, Flotte T R, Nick H S (2012). Induction of group IVC phospholipase A2 in allergic asthma: transcriptional regulation by TNFα in bronchoepithelial cells. Biochem J, 442(1): 127–137

    Article  PubMed  CAS  Google Scholar 

  • Chi P L, Luo S F, Hsieh H L, Lee I T, Hsiao L D, Chen Y L, Yang C M (2011). Cytosolic phospholipase A2 induction and prostaglandin E2 release by interleukin-1β via the myeloid differentiation factor 88-dependent pathway and cooperation of p300, Akt, and NF-κB activity in human rheumatoid arthritis synovial fibroblasts. Arthritis Rheum, 63(10): 2905–2917

    Article  PubMed  CAS  Google Scholar 

  • Clemens J A, Stephenson D T, Smalstig E B, Roberts E F, Johnstone E M, Sharp J D, Little S P, Kramer R M (1996). Reactive glia express cytosolic phospholipase A2 after transient global forebrain ischemia in the rat. Stroke, 27(3): 527–535

    Article  PubMed  CAS  Google Scholar 

  • Cowan M J, Yao X L, Pawliczak R, Huang X, Logun C, Madara P, Alsaaty S, Wu T, Shelhamer J H (2004). The role of TFIID, the initiator element and a novel 5′ TFIID binding site in the transcriptional control of the TATA-less human cytosolic phospholipase A2-alpha promoter. Biochim Biophys Acta, 1680(3): 145–157

    Article  PubMed  CAS  Google Scholar 

  • Farooqui A A (2010). Studies on plasmalogen-selective phospholipase A2 in. Mol Neurobiol, 41(2–3): 267–273

    Article  PubMed  CAS  Google Scholar 

  • Farooqui A A, Antony P, Ong W Y, Horrocks L A, Freysz L (2004). Retinoic acid-mediated phospholipase A2 signaling in the nucleus. Brain Res Brain Res Rev, 45(3): 179–195

    Article  PubMed  CAS  Google Scholar 

  • Farooqui A A, Ong W Y, Farooqui T (2010). Lipid mediators in the nucleus: Their potential contribution to Alzheimer’s disease. Biochim Biophys Acta, 1801(8): 906–916

    Article  PubMed  CAS  Google Scholar 

  • Farooqui A A, Ong W Y, Horrocks L A (2006). Inhibitors of brain phospholipase A2 activity: their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders. Pharmacol Rev, 58(3): 591–620

    Article  PubMed  CAS  Google Scholar 

  • Farooqui A A, Ong W Y, Horrocks L A, Farooqui T (2000). Brain cytosolic phospholipase A2: Localization, role, and involvement in neurological diseases. Neuroscientist, 6(3): 169–180

    Article  CAS  Google Scholar 

  • Farooqui A A, Yang H C, Rosenberger T A, Horrocks L A (1997). Phospholipase A2 and its role in brain tissue. J Neurochem, 69(3): 889–901

    Article  PubMed  CAS  Google Scholar 

  • Fitzpatrick J S, Baudry M (1994). Blockade of long-term depression in neonatal hippocampal slices by a phospholipase A2 inhibitor. Brain Res Dev Brain Res, 78(1): 81–86

    Article  PubMed  CAS  Google Scholar 

  • Fujita S, Ikegaya Y, Nishikawa M, Nishiyama N, Matsuki N (2001). Docosahexaenoic acid improves long-term potentiation attenuated by phospholipase A(2) inhibitor in rat hippocampal slices. Br J Pharmacol, 132(7): 1417–1422

    Article  PubMed  CAS  Google Scholar 

  • Gregory A, Westaway S K, Holm I E, Kotzbauer P T, Hogarth P, Sonek S, Coryell J C, Nguyen T M, Nardocci N, Zorzi G, Rodriguez D, Desguerre I, Bertini E, Simonati A, Levinson B, Dias C, Barbot C, Carrilho I, Santos M, Malik I, Gitschier J, Hayflick S J (2008). Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology, 71(18): 1402–1409

    Article  PubMed  CAS  Google Scholar 

  • Gubern A, Barceló-Torns M, Barneda D, López J M, Masgrau R, Picatoste F, Chalfant C E, Balsinde J, Balboa M A, Claro E (2009). JNK and ceramide kinase govern the biogenesis of lipid droplets through activation of group IVA phospholipase A2. J Biol Chem, 284 47): 32359–32369

    Article  Google Scholar 

  • Guo C, Li J, Myatt L, Zhu X, Sun K (2010). Induction of Galphas contributes to the paradoxical stimulation of cytosolic phospholipase A2alpha expression by cortisol in human amnion fibroblasts. Mol Endocrinol, 24(5): 1052–1061

    Article  PubMed  CAS  Google Scholar 

  • Huang W, Bhavsar A, Ward R E, Hall J C, Priestley J V, Michael-Titus A T (2009). Arachidonyl trifluoromethyl ketone is neuroprotective after spinal cord injury. J Neurotrauma, 26(8): 1429–1434

    Article  PubMed  Google Scholar 

  • Jenkins C M, Mancuso D J, Yan W, Sims H F, Gibson B, Gross R W (2004). Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem, 279(47): 48968–48975

    Article  PubMed  CAS  Google Scholar 

  • Kurian M A, Morgan N V, MacPherson L, Foster K, Peake D, Gupta R, Philip S G, Hendriksz C, Morton J E, Kingston H M, Rosser E M, Wassmer E, Gissen P, Maher E R (2008). Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 ene (PLAN). Neurology, 70(18): 1623–1629

    Article  PubMed  CAS  Google Scholar 

  • Kusenda B, Mraz M, Mayer J, Pospisilova S (2006). MicroRNA biogenesis, functionality and cancer relevance. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 150(2): 205–215

    Article  PubMed  CAS  Google Scholar 

  • Larsson Forsell P K, Kennedy B P, Claesson H E (1999). The human calcium-independent phospholipase A2 gene multiple enzymes with distinct properties from a single gene. Eur J Biochem, 262(2): 575–585

    Article  PubMed  CAS  Google Scholar 

  • Lee C W, Lee I T, Lin C C, Lee H C, Lin W N, Yang C M (2010). Activation and induction of cytosolic phospholipase A2 by IL-1beta in human tracheal smooth muscle cells: role of MAPKs/p300 nd NF-kappaB. J Cell Biochem, 109(5): 1045–1056

    PubMed  CAS  Google Scholar 

  • Lee C W, Lin C C, Lee I T, Lee H C, Yang C M (2011). Activation and induction of cytosolic phospholipase A2 by TNF-α mediated through Nox2, MAPKs, NF-κand p300 n human tracheal smooth muscle cells. J Cell Physiol, 226(8): 2103–2114

    Article  PubMed  CAS  Google Scholar 

  • Lee L H, Shui G, Farooqui A A, Wenk M R, Tan C H, Ong W Y (2009a). Lipidomic analyses of the mouse brain after antidepressant treatment: evidence for endogenous release of long-chain fatty acids? Int J Neuropsychopharmacol, 12(7): 953–964

    Article  PubMed  CAS  Google Scholar 

  • Lee L H, Tan C H, Shui G, Wenk M R, Ong W Y (2012). Role of prefrontal cortical calcium independent phospholipase A2 in antidepressant-like effect of maprotiline. Int J Neuropsychopharmacol, 15(8): 1087–1098

    Article  PubMed  CAS  Google Scholar 

  • Lee L Y, Farooqui A A, Dawe G S, Burgunder J M, Ong W Y (2009b). Role of phospholipase A(2) in prepulse inhibition of the auditory startle reflex in rats. Neurosci Lett, 453(1): 6–8

    Article  PubMed  CAS  Google Scholar 

  • Li X, Stark G R (2002). NFrB-dependent signaling pathways. Exp Hematol, 30(4): 285–296

    Article  PubMed  CAS  Google Scholar 

  • Liao W L, Wang W C, Chang W C, Tseng J T (2011). The RNA-binding protein HuR stabilizes cytosolic phospholipase A2α mRNA under interleukin-1β treatment in non-small cell lung cancer A549 Cells. J Biol Chem, 286(41): 35499–35508

    Article  PubMed  CAS  Google Scholar 

  • Lin C C, Lin W N, Cheng S E, Tung W H, Wang H H, Yang CM (2012). Transactivation of EGFR/PI3K/Akt involved in ATP-induced inflammatory protein expression and cell motility. J Cell Physiol, 227(4): 1628–1638

    Article  PubMed  CAS  Google Scholar 

  • Lu X R, Ong W Y, Halliwell B, Horrocks L A, Farooqui A A (2001). Differential effects of calcium-dependent and calcium-independent phospholipase A(2) inhibitors on kainate-induced neuronal injury in rat hippocampal slices. Free Radic Biol Med, 30(11): 1263–1273

    Article  PubMed  CAS  Google Scholar 

  • Ma Z, Turk J (2001). The molecular biology of the group VIA Ca2+-independent phospholipase A2. Prog Nucleic Acid Res Mol Biol, 67: 1–33

    Article  PubMed  CAS  Google Scholar 

  • Ma Z, Wang X, Nowatzke W, Ramanadham S, Turk J (1999). Human pancreatic islets express mRNA species encoding two distinct catalytically active isoforms of group VI phospholipase A2 (iPLA2) that arise from an exon-skipping mechanism of alternative splicing of the transcript from the iPLA2 gene on chromosome 22q13.1. J Biol Chem, 274(14): 9607–9616

    Article  PubMed  CAS  Google Scholar 

  • Mascaró C, Ortiz J A, Ramos M M, Haro D, Hegardt F G (2000). Sterol regulatory element binding protein-mediated effect of fluvastatin on cytosolic 3-hydroxy-3-methylglutaryl-coenzyme A synthase transcription. Arch Biochem Biophys, 374(2): 286–292

    Article  PubMed  Google Scholar 

  • Maxwell A P, Goldberg H J, Tay A H, Li Z G, Arbus G S, Skorecki K L (1993). Epidermal growth factor and phorbol myristate acetate increase expression of the mRNA for cytosolic phospholipase A2 in glomerular mesangial cells. Biochem J, 295(Pt 3): 763–766

    PubMed  CAS  Google Scholar 

  • Morgan N V, Westaway S K, Morton J E, Gregory A, Gissen P, Sonek S, Cangul H, Coryell J, Canham N, Nardocci N, Zorzi G, Pasha S, Rodriguez D, Desguerre I, Mubaidin A, Bertini E, Trembath R C, Simonati A, Schanen C, Johnson C A, Levinson B, Woods C G, Wilmot B, Kramer P, Gitschier J, Maher E R, Hayflick S J (2006). PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet, 38(7): 752–754

    Article  PubMed  CAS  Google Scholar 

  • Morri H, Ozaki M, Watanabe Y (1994). 5′-flanking region surrounding a human cytosolic phospholipase A2 gene. Biochem Biophys Res Commun, 205(1): 6–11

    Article  PubMed  CAS  Google Scholar 

  • Murakami M, Taketomi Y, Miki Y, Sato H, Hirabayashi T, Yamamoto K (2011a). Recent progress in phospholipase A2 research: from cells to animals to humans. Prog Lipid Res, 50(2): 152–192

    Article  PubMed  CAS  Google Scholar 

  • Murakami M, Taketomi Y, Sato H, Yamamoto K (2011b). Secreted phospholipase A2 revisited. J Biochem, 150(3): 233–255

    Article  PubMed  CAS  Google Scholar 

  • Ong W Y, Farooqui T, Farooqui A A (2010). Involvement of cytosolic phospholipase A(2), calcium independent phospholipase A(2) and plasmalogen selective phospholipase A(2) in neurodegenerative and neuropsychiatric conditions. Curr Med Chem, 17(25): 2746–2763

    Article  PubMed  CAS  Google Scholar 

  • Ong W Y, Lu X R, Ong B K, Horrocks L A, Farooqui A A, Lim S K (2003). Quinacrine abolishes increases in cytoplasmic phospholipase A2 mRNA levels in the rat hippocampus after kainate-induced neuronal injury. Exp Brain Res, 148(4): 521–524

    PubMed  CAS  Google Scholar 

  • Ong W Y, Sandhya T L, Horrocks L A, Farooqui A A (1999). Distribution of cytoplasmic phospholipase A2 in the normal rat brain. J Hirnforsch, 39(3): 391–400

    PubMed  Google Scholar 

  • Ong W Y, Yeo J F, Ling S F, Farooqui A A (2005). Distribution of calcium-independent phospholipase A2 (iPLA2) in monkey brain. J Neurocytol, 34(6): 447–458

    Article  PubMed  CAS  Google Scholar 

  • Owada Y, Tominaga T, Yoshimoto T, Kondo H (1994). Molecular cloning of rat cDNA for cytosolic phospholipase A2 and the increased gene expression in the dentate gyrus following transient forebrain ischemia. Brain Res Mol Brain Res, 25(3–4): 364–368

    Article  PubMed  CAS  Google Scholar 

  • Phillis J W, O’Regan M H (1996). Mechanisms of glutamate and aspartate release in the ischemic rat cerebral cortex. Brain Res, 730(1–2): 150–164

    PubMed  CAS  Google Scholar 

  • Quistad G B, Barlow C, Winrow C J, Sparks S E, Casida J E (2003). Evidence that mouse brain neuropathy target esterase is a lysophospholipase. Proc Natl Acad Sci USA, 100(13): 7983–7987

    Article  PubMed  CAS  Google Scholar 

  • Reed K A, Tucker D E, Aloulou A, Adler D, Ghomashchi F, Gelb M H, Leslie C C, Oates J A, Boutaud O (2011). Functional characterization of mutations in inherited human cPLA2 deficiency. Biochemistry, 50(10): 1731–1738

    Article  PubMed  CAS  Google Scholar 

  • Roglans N, Verd J C, Peris C, Alegret M, Vázquez M, Adzet T, Díaz C, Hernández G, Laguna J C, Sánchez R M (2002). High doses of atorvastatin and simvastatin induce key enzymes involved in VLDL production. Lipids, 37(5): 445–454

    Article  PubMed  CAS  Google Scholar 

  • Sandhya T L, Ong W Y, Horrocks L A, Farooqui A A (1998). A light and electron microscopic study of cytoplasmic phospholipase A2 and cyclooxygenase-2 in the hippocampus after kainate lesions. Brain Res, 788(1–2): 223–231

    Article  PubMed  CAS  Google Scholar 

  • Schaeffer E L, da Silva E R, Novaes B A, Skaf H D, Gattaz W F (2010). Differential roles of phospholipases A2 in neuronal death and neurogenesis: implications for Alzheimer disease. Prog Neuropsychopharmacol Biol Psychiatry, 34(8): 1381–1389

    Article  PubMed  CAS  Google Scholar 

  • Seashols S J, del Castillo Olivares A, Gil G, Barbour S E (2004). Regulation of group VIA phospholipase A2 expression by sterol availability. Biochim Biophys Acta, 1684(1–3): 29–37

    PubMed  CAS  Google Scholar 

  • Sundaram J R, Chan E S, Poore C P, Pareek T K, Cheong W F, Shui G, Tang N, Low C M, Wenk M R, Kesavapany S (2012). Cdk5/p25-induced cytosolic PLA2-mediated lysophosphatidylcholine production regulates neuroinflammation and triggers neurodegeneration. J Neurosci, 32(3): 1020–1034

    Article  PubMed  CAS  Google Scholar 

  • Takai D, Jones P A (2003). The CpG island searcher: a new www resource. In Silico Biol, 3(3): 235–240

    PubMed  CAS  Google Scholar 

  • Talbot K, Young R A, Jolly-Tornetta C, Lee VM, Trojanowski J Q, Wolf B A (2000). A frontal variant of Alzheimer’s disease exhibits decreased calcium-independent phospholipase A2 activity in the prefrontal cortex. Neurochem Int, 37(1): 17–31

    Article  PubMed  CAS  Google Scholar 

  • Tang J, Kriz R W, Wolfman N, Shaffer M, Seehra J, Jones S S (1997). A novel cytosolic calcium-independent phospholipase A2 contains eight ankyrin motifs. J Biol Chem, 272(13): 8567–8575

    Article  PubMed  CAS  Google Scholar 

  • Tay A, Maxwell P, Li Z G, Goldberg H, Skorecki K (1994). Cytosolic phospholipase A2 gene expression in rat mesangial cells is regulated post-transcriptionally. Biochem J, 304(Pt 2): 417–422

    PubMed  CAS  Google Scholar 

  • Tomiyama H, Yoshino H, Ogaki K, Li L, Yamashita C, Li Y, Funayama M, Sasaki R, Kokubo Y, Kuzuhara S, Hattori N (2011). PLA2G6 variant in Parkinson’s disease. J Hum Genet, 56(5): 401–403

    Article  PubMed  CAS  Google Scholar 

  • Tsou J H, Chang K Y, Wang W C, Tseng J T, Su W C, Hung L Y, Chang W C, Chen B K (2008). Nucleolin regulates c-Jun/Sp1-dependent transcriptional activation of cPLA2alpha in phorbol ester-treated non-small cell lung cancer A549 cells. Nucleic Acids Res, 36(1): 217–227

    Article  PubMed  CAS  Google Scholar 

  • Umeno J, Matsumoto T, Esaki M, Kukita Y, Tahira T, Yanaru-Fujisawa R, Nakamura S, Arima H, Hirahashi M, Hayashi K, Iida M (2010). Impact of group IVA cytosolic phospholipase A2 gene polymorphisms on phenotypic features of patients with familial adenomatous polyposis. Int J Colorectal Dis, 25(3): 293–301

    Article  PubMed  Google Scholar 

  • Wolf M J, Izumi Y, Zorumski C F, Gross R W (1995). Long-term potentiation requires activation of calcium-independent phospholipase A2. FEBS Lett, 377(3): 358–362

    Article  PubMed  CAS  Google Scholar 

  • Wu T, Ikezono T, Angus C W, Shelhamer J H (1994a). Characterization of the promoter for the human 85 kDa cytosolic phospholipase A2 gene. Nucleic Acids Res, 22(23): 5093–5098

    Article  PubMed  CAS  Google Scholar 

  • Wu T, Levine S J, Lawrence M G, Logun C, Angus CW, Shelhamer J H (1994b). Interferon-gamma induces the synthesis and activation of cytosolic phospholipase A2. J Clin Invest, 93(2): 571–577

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neurobiology and Ageing Research Programme, National University of Singapore, Singapore, 117456, Singapore

    Kazuhiro Tanaka & Wei-Yi Ong

  2. Department of Biochemistry, College of Science, King Saud University, Riyadh, 1145,1, Saudi Arabia

    Nikhat J. Siddiqi & Abdullah S. Alhomida

  3. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, 43210, USA

    Akhlaq A. Farooqui

  4. Department of Anatomy, National University of Singapore, Singapore, 119260, Singapore

    Wei-Yi Ong

Authors
  1. Kazuhiro Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nikhat J. Siddiqi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abdullah S. Alhomida
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akhlaq A. Farooqui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei-Yi Ong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei-Yi Ong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tanaka, K., Siddiqi, N.J., Alhomida, A.S. et al. Differential regulation of cPLA2 and iPLA2 expression in the brain. Front. Biol. 7, 514–521 (2012). https://doi.org/10.1007/s11515-012-9247-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-012-9247-0

Keywords

Search

Navigation