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

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 (cPLA₂) in PGE₂ production was investigated by comparing lung fibroblasts from wild-type and cPLA₂-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-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 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-, cPLA₂ • 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-, TNF-

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