Eosinophil cysteinyl leukotriene synthesis mediated by exogenous secreted phospholipase A2 group X.

Abstract

Secreted phospholipase A(2) group X (sPLA(2)-X) has recently been identified in the airways of patients with asthma and may participate in cysteinyl leukotriene (CysLT; C(4), D(4), and E(4)) synthesis. We examined CysLT synthesis and arachidonic acid (AA) and lysophospholipid release by eosinophils mediated by recombinant human sPLA(2)-X. We found that recombinant sPLA(2)-X caused marked AA release and a rapid onset of CysLT synthesis in human eosinophils that was blocked by a selective sPLA(2)-X inhibitor. Exogenous sPLA(2)-X released lysophospholipid species that arise from phospholipids enriched in AA in eosinophils, including phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine as well as plasmenyl phosphatidylcholine and phosphatidylethanolamine. CysLT synthesis mediated by sPLA(2)-X but not AA release could be suppressed by inhibition of cPLA(2)α. Exogenous sPLA(2)-X initiated Ser(505) phosphorylation of cPLA(2)α, an intracellular Ca(2+) flux, and translocation of cPLA(2)α and 5-lipoxygenase in eosinophils. Synthesis of CysLTs in response to sPLA(2)-X or lysophosphatidylcholine was inhibited by p38 or JNK inhibitors but not by a MEK 1/2 inhibitor. A further increase in CysLT synthesis was induced by the addition of sPLA(2)-X to eosinophils under conditions of N-formyl-methionyl-leucyl-phenylalanine-mediated cPLA(2)α activation. These results indicate that sPLA(2)-X participates in AA and lysophospholipid release, resulting in CysLT synthesis in eosinophils through a mechanism involving p38 and JNK MAPK, cPLA(2)α, and 5-lipoxygenase activation and resulting in the amplification of CysLT synthesis during cPLA(2)α activation. Transactivation of eosinophils by sPLA(2)-X may be an important mechanism leading to CysLT formation in the airways of patients with asthma.

• Authors: Ying Lai, Rob C Oslund, James G Bollinger, William R Henderson Jr, Luis F Santana, William A Altemeier, Michael H Gelb, Teal S Hallstrand
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 53 Pg. 41491-500 (Dec 31 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20974857 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Eicosanoids
• Leukotrienes
• Lysophospholipids
• Recombinant Proteins
• cysteinyl-leukotriene
• Serine
• N-Formylmethionine Leucyl-Phenylalanine
• p38 Mitogen-Activated Protein Kinases
• Group X Phospholipases A2
• PLA2G10 protein, human
• Phospholipases A2
• Cysteine
• Calcium

Topics

• Asthma (drug therapy)
• Calcium (chemistry)
• Cysteine (biosynthesis)
• Eicosanoids (chemistry)
• Eosinophils (enzymology, metabolism)
• Group X Phospholipases A2 (chemistry)
• Humans
• Leukotrienes (biosynthesis, chemistry)
• Lysophospholipids (chemistry)
• N-Formylmethionine Leucyl-Phenylalanine (pharmacology)
• Phospholipases A2 (metabolism)
• Phosphorylation
• Recombinant Proteins (chemistry)
• Serine (chemistry)
• p38 Mitogen-Activated Protein Kinases (metabolism)