The action of the mast cell product tryptase on cyclooxygenase-2 (COX2) and subsequent fibroblast proliferation involves activation of the extracellular signal-regulated kinase isoforms 1 and 2 (erk1/2)

• Published in: Cellular signalling 2005-04, Vol.17 (4), p.525-533
• Main Authors: Frungieri, Mónica B., Albrecht, Martin, Raemsch, Romi, Mayerhofer, Artur
• Format: Article
• Language: English
• Subjects: Base Sequence; Ca 2; Calcium - metabolism; cAMP; Cell Proliferation; Cyclic AMP - metabolism; Cyclooxygenase 2; Fibroblasts - cytology; Fibroblasts - enzymology; Human immunodeficiency virus 2; Humans; Male; MAP kinases; Mast Cells - enzymology; Membrane Proteins; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular Sequence Data; Prostaglandin-Endoperoxide Synthases - metabolism; Protein Isoforms - metabolism; Serine Endopeptidases - metabolism; Signal Transduction; Transcription factors; Tryptase; Tryptases; Up-Regulation
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2004.09.017

The mast cell product tryptase, via protease-activated receptor 2 (PAR2), induces cyclooxygenase-2 (COX2) and 15-deoxy-prostaglandin J2 (15d-PGJ2) synthesis. 15d-PGJ2, through the nuclear peroxisome proliferator activated receptor gamma (PPARγ), subsequently causes fibroblast proliferation. In this study we attempted to determine initial events of the tryptase/PAR2 signaling pathway leading to COX2 induction and fibroblast proliferation. In human fibroblasts (HFFF2), cDNA array, RT-PCR and Western blotting studies demonstrated that tryptase, but not 15d-PGJ2, up-regulates c-jun, c-fos and COX2 expression, and phosphorylates the extracellular signal-regulated kinase isoforms 1 and 2 (erk1/2). Furthermore, tryptase effects on erk1/2, c-jun, c-fos, COX2 and cell proliferation were prevented by PD98059, an inhibitor of the mitogen-activated protein kinase kinase (MEK). Other kinases [P38, stress-activated protein kinase/ c-jun N-terminal kinase (SAPK/JUNK), erk5], intracellular Ca 2+ or cAMP were not affected by tryptase/PAR2. Our study identifies crucial intracellular events leading to induction of COX2 and fibroblast proliferation, i.e. a cornerstone of fibrosis.