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Published ahead of print on July 3, 2003, doi:10.1165/rcmb.2003-0005OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 30, pp. 91-100, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2003-0005OC

Role of Cytosolic Phospholipase A2 in Prostaglandin E2 Production by Lung Fibroblasts

Moumita Ghosh, Allison Stewart, Dawn E. Tucker, Joseph V. Bonventre, Robert C. Murphy and Christina C. Leslie

Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver; Departments of Pathology and Pharmacology, University of Colorado School of Medicine, Denver, Colorado; Department of Medicine, Harvard Medical School, Massachusetts General Hospital East, Charlestown, Massachusetts; and Astra Zeneca R&D Charnwood, Safety Assessment, Loughborough, United Kingdom

Address correspondence to: Christina C. Leslie, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. E-mail: lesliec{at}njc.org

Prostaglandin (PG)E2 acts in an autocrine fashion to suppress proliferation of lung fibroblasts and production of collagen, and may negatively regulate pulmonary fibrosis. The role of Group IVA cytosolic phospholipase A2 {alpha} (cPLA2{alpha}) in PGE2 production was investigated by comparing lung fibroblasts from wild-type and cPLA2{alpha}-deficient mice. 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 >= 80% lower from cPLA2{alpha}-deficient MLF (MLF-/-). Transforming growth factor-ß increased cyclooxygenase-2 (COX2) expression to similar levels in MLF+/+ and MLF-/-, but MLF+/+ produced an order of magnitude more PGE2 than MLF-/- in response to A23187/PMA or platelet-derived growth factor/LPA. MLF+/+ synthesized less collagen than MLF-/-, supporting a role for PGE2 in suppressing collagen production. An SV40 immortalized line developed from MLF+/+ released arachidonic acid and expressed COX2 to levels similar to those of primary fibroblasts but produced 30-fold lower amounts of PGE2. Unlike primary fibroblasts, immortalized cells were deficient in microsomal PGE synthase (mPGES) but expressed slightly higher levels of cytosolic PGES. 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.

Abbreviations: 5-lipoxygenase, 5-LO • cyclooxygenase-2, COX2 • cytosolic PGES, cPGES • cytosolic PLA2-{alpha}, cPLA2{alpha} • Dulbecco's modified Eagle's medium, DMEM • extracellular matrix, ECM • fetal bovine serum, FBS • interleukin, IL • immortalized MLF, IMLF • lysophosphatidic acid, LPA • mitogen-activated protein kinases, MAPK • mouse lung fibroblasts, MLF • microsomal prostaglandin E synthase, mPGES • polymerase chain reaction, PCR • platelet-derived growth factor, PDGF • prostaglandin, PG • protein kinase C, PKC • phospholipase A2, PLA2 • phorbol-myristate acetate, PMA • sodium dodecyl sulfate, SDS • transforming growth factor-ß, TGF-ß • tumor necrosis factor-{alpha}, TNF-{alpha}




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