Role of melittin-like region within phospholipase A(2)-activating protein in biological function.
Phospholipase A(2)-activating protein (PLAA) has been implicated in the production of prostaglandins (e.g. PGE(2)) via activation of phospholipases in various stimulated cell types. Human PLAA, with 738 amino acid (aa) residues, contains a region of 38% homology (aa 503-538) with the 26-aa long melittin peptide, a major component of bee venom and a reported regulator of phospholipase A(2) and phospholipase D activity. To learn more about the role of PLAA in the production of eicosanoids and other inflammatory mediators, we synthesized a murine PLAA peptide (36-aa long) having homology to melittin, as well as to human and rat PLAA. The PLAA peptide and melittin increased the expression of genes encoding the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) and cyclooxygenase-2 (COX-2), which is involved in PGE(2) production. We determined that the C-terminal region of the PLAA peptide (aa 515-538) was essential, since truncation of the C-terminal end of the PLAA peptide significantly reduced expression of genes encoding TNFalpha and COX-2 in macrophages. We concluded that PLAA could be important in the regulation of the inflammatory response because of its stimulatory effects on eicosanoid and cytokine synthesis. Consequently, control of plaa gene expression could be a target for the development of new drugs to control the inflammatory response.
Ribardo
Deborah A
DA
Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1070, USA.
Kuhl
Kristine R
KR
Peterson
Johnny W
JW
Chopra
Ashok K
AK
D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008555:Melitten / Q000031:analogs & derivatives / Q000235:genetics / Q000494:pharmacology*; D008565:Membrane Proteins; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D010739:Phospholipase D / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D007527:Isoenzymes; D008565:Membrane Proteins; D010446:Peptide Fragments; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C055324:phospholipase A2-activating protein; D008555:Melitten; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D010739:Phospholipase D; D015232:Dinoprostone