• Bernard Rothhut
  • Françoise Russo-Marie
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 245)


The various membrane events occuring during the inflammatory reaction and leading to the formation of lipid-derived mediators (prostaglandins, leukotrienes and PAF-acether) always involve a membrane enzyme activation namely phospholipase A2. This activation leads to the cleavage of the phospholipids present in the membrane and permits the release of an unsaturated fatty acid from the 2 position - usually, arachidonic acid - and to the simultaneous formation of a lysophospholipid. If the phospholipase A2-target phospholipid is an ether phosphatidyl choline, the lyso derivative formed is lyso PAF, the precursor of PAF-acether (Platelet Activating Factor, 1-0- alkyl- 2 - acetyl - sn- glycero- 3 - phosphocholine) (Figure 1). In inflammatory cells, the signal induced by inflammatory stimuli is transduced by a succession of events leading to the phospholipase A2 stimulation, allowing consequently the release in the cell of either arachidonic acid, precursor of prostaglandins and leukotrienes, or lyso-PAF, precursor of PAF-acether. These products, once formed, leave the cell and are able to stimulate neighbouring cell membranes, inducing again phospholipase A2 stimulation through stimulus-coupling events. An oversimplified view of the inflammatory reaction can be presented as an event stimulating the membrane of inflammatory cells, event coupled to transducing systems allowing the formation of lipid-derived mediators. These mediators, being stimuli by themselves amplify the phenomenon, rendering the inflammatory reaction rather similar to a nuclear reaction where the pile is phospholipase A2, and the combustible, phospholipids, always renewed by powerful acylating systems. Would phospholipase A2 be alone, the reaction would be endless and could become harmful for the biological environment where it takes place. Consequently, there must be some naturally occuring biological systems capable of controlling such a reaction. The discovery of lipocortin, a natural endogenous phospholipase A2 inhibitor, has focused the attention on the central role of pnospholipase A2 in the inflammatory reaction. Indeed, this discovery has been linked to the knowledge of the biochemical and cellular mode of action of glucocorticosteroids, which inhibit phospholipase A2 activity through the induction of the synthesis of lipocortin (Figure 2).


Inositol Triphosphate Epidermal Growth Factor Receptor Kinase Murine Thymocyte Tyrosine Kinase Substrate Rabbit Neutrophil 
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  1. 1.
    Blackwell GJ, Carnuccio R, DiRosa M, Flower RJ, Parente L, Persico P. Macrocortin: a polypeptide causing the antiphospholipase like effects of glucocorticoids. Nature 1980; 287: 147–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Hirata F, Schiffmann D, Venkatasubramanian K, Salomon D, Axelrod J. A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticosteroids. Proc Natl Acad Sci USA 1980; 77: 2533–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Cloix JF, Colard O, Rothhut B, Russo-Marie F. Characterization and partial purification of “renocortins”: two polypeptides formed in renal cells causing the antiphospholipase like action of glucocorticoids. Br J Pharmacol 1983; 79: 312–21.CrossRefGoogle Scholar
  4. 4.
    DiRosa M, Flower RJ, Hirata F, Parente L, Russo-Marie F. Lipocortins, nomenclature announcement. Prostaglandins 1984; 28: 441–4Google Scholar
  5. 5.
    Hirata F. The regulation of lipomodulin, a phospholipase inhibitory protein, in rabbit neutrophils by phosphorylation. J Biol Chem 1981; 256: 7730–3.PubMedGoogle Scholar
  6. 6.
    Rothhut B, Russo-Marie F, Cousin M, Lando D. Renocortin: a phospholipase A2 inhibitory protein induced by anti-inflammatory steroids: pharmacological and biological properties, development of monoclonal antibodies. In Proceedings of the 9th IUPHAR Congress of Pharmacology, P Turner, W Paton, JF Mitchell (eds), The Macmillan Press ltd. London, 1984: 43–6Google Scholar
  7. 7.
    Hirata F, Matsuda K, Notsu Y, Hattori T, DelCarmine R. Phosphorylation of a tyrosine residue of lipomodulin in mitogen-stimulated murine thymocytes. Proc Natl Acad Sci USA 1984; 81: 4717–21.PubMedCrossRefGoogle Scholar
  8. 8.
    Touqui L, Rothhut B, Shaw A, Fradin A, Vargaftig BB, Russo-Marie F. Platelet activation-a role for a 40 K antiphospholipase A2 protein indistinguishable from lipocortin. Nature 1986; 321: 177–80.PubMedCrossRefGoogle Scholar
  9. 9.
    Blake-Pepinsky R, Sinclair LK, Browning JL et al. Purification and partial sequence analysis of a 37 KDa protein that inhibits phospholipase A2 activity from rat peritoneal exudates. J Biol Chem 1986; 261: 4246–9.Google Scholar
  10. 10.
    Wallner BP, Mattaliano RJ, Hession C et al.: Cloning and expression of human lipocortin, a phospholipase A2 inhibitor with potential anti-inflammatory activity. Nature 1986; 320: 77–80.PubMedCrossRefGoogle Scholar
  11. 11.
    Blake-Pepinsky R, Sinclair LK. Epidermal growth factor-dependent phosphorylation of lipocortin. Nature 1986; 321: 81–84.CrossRefGoogle Scholar
  12. 12.
    Huang K-S, Wallner BP, Mattaliano RJ, Browning JL et al. Two human 35 KD inhibitors of phospholipase A2 are related to substrates of pp60 srcfr and of epidermal growth factor receptor kinase. Cell 1986; 46: 191–9.PubMedCrossRefGoogle Scholar
  13. 13.
    De BK, Misono KS, Lukas TJ, Mroczkowski B, Cohen S. A calcium-dependent 35-kilodalton substrate for epidermal growth factor receptor/kinase isolated from normal tissue. J Biol Chem 1986; 261: 13784–92.PubMedGoogle Scholar
  14. 14.
    Glenney JR, Jr. Two related but different forms of the 36,000 Mr tyrosine kinase substrate (calpactins) which interact with phospholipid and actin in a Ca+fr-dependent manner. Proc Natl Acad Sci USA 1986; 83: 4258–62.PubMedCrossRefGoogle Scholar
  15. 15.
    Kristensen T, Saris CJM, Hunter T, Hicks LJ, Noonan DJ, Glenney JR, Tack B. Primary structure of bovine calpactin I heavy chain (p36), a major cellular substrate for retroviral protein-tyrosine kinases: homology with the human phospholipase A2 inhibitor lipocortin. Biochemistry 1986; 25: 4497–503.PubMedCrossRefGoogle Scholar
  16. 16.
    Saris CJM, Tack BF, Kristensen T, Glenney JR, Hunter T. The cDNA sequence for the protein tyrosine kinase substrate p36 (Calpactin I heavy chain) reveals a multidomain protein with internal repeats. Cell 1986; 46: 201–12.PubMedCrossRefGoogle Scholar
  17. 17.
    Geisow MJ, Fritsche U, Hexham JM, Dash B, Johnson T. A consensus amino-acid sequence repeat in Torpedo and mammalian Ca+dependent membrane-binding proteins. Nature 1986; 320: 636–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Geisow MJ. Common domain structures of Ca+fr and lipid-binding proteins. FEBS Lett 1986; 203: 99–103.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Bernard Rothhut
    • 1
  • Françoise Russo-Marie
    • 1
  1. 1.Unité des VeninsUnité Associée Institut Pasteur / INSERM N0 285Paris Cedex 15France

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